Pyrimidine derivatives

ABSTRACT

The present invention is directed to a pyrimidine derivative of the following formula (1) or a salt of the derivative: ##STR1## [wherein R 1  represents a lower alkyl group; each of R 2  and R 3  represents H, alkyl, or alkoxy; each of R 4  and R 5  represents H or alkyl; R 6  represents alkyl, --OR 7 , or --NR 8  R 9  ; and n is a number between 0 and 3 inclusive (wherein each of R 7 , R 8 , and R 9  represents H, alkyl, aryl, aralkyl, amino, a heterocyclic ring, etc.)], as well as to a medicine containing the derivative or salt as the active ingredient. The present compounds exhibit strong binding inhibitory activity against endothelin having potent vasoconstrictive effect and cell proliferation effect. Therefore, the compounds are effective as remedies for various diseases including circulatory diseases.

TECHNICAL FIELD

The present invention relates to novel pyrimidine derivatives and theirsalts, and to pharmaceuticals containing these compounds as activeingredients.

BACKGROUND ART

Endothelin, having potent vasoconstrictive effect, blood pressureelevating effect, and cell proliferation effect, is considered to be asubstance that contributes to various diseases and disorders includingheart diseases such as ischemic heart infarction, congestive heartfailure, arrhythmia, and unstable angina; airway diseases such asasthma; hypertonia such as pulmonary hypertension, renal hypertension,and hypertension accompanying organ transplantation; circulatorydiseases such as subarachnoid hemorrhage and post-PTCA reconstriction orvasospasm; kidney diseases such as acute and chronic renal failure;diabetes, hyperlipemia, and other diseases that are accompanied byvascular lesion, as well as arteriosclerosis; liver diseases such asalcohol-induced liver disorders; gastrointestinal disorders such asthose of gastric mucosa; bone diseases; prostatic hypertrophy andurinary disorders; cancer; and skin diseases concurrent withproliferation of melanocytes [Saishin-Igaku (may be translated to"Medicine Up-to-date"), 94, 335-431(1994), Igaku-no-Ayumi (may betranslated to "Progress of Medicine"), 168, 675-692(1994),Igaku-no-Ayumi, 170, 357(1994), Pharmac. Rev., 46, 325(1994), andGendai-Iryo (may be translated to "Modern Remedies"), 27, 1 (1995)].

It has come to be elucidated that a variety of actions of endothelin aretriggered upon binding of endothelin to its receptors in organs of thebody, and that the vasoconstriction caused by endothelin is induced bythe mediation of at least two different receptors (ET_(A) receptor andET_(B) receptor). Therefore, a compound that prevents endothelin frombinding to these two receptors should be useful as a preventive andtherapeutic agent for the above-mentioned diseases in which endothelinparticipates. Heretofore, a number of compounds have been reported asexhibiting endothelin antagonism [J. Med. Chem., 36, 2585 (1993),Nature, 365, 759(1993), Circulation, 88, 1-316 (1994), Saishin-Igaku,94, 424-431(1994), J. Med. Chem. 37, 1553(1994), and Japanese PatentApplication Laid-Open (kokai) No. 5-222003)].

However, there have not yet been found compounds that exhibitsatisfactory endothelin antagonism.

Accordingly, the present invention is directed to the discovery of acompound that has potent endothelin antagonism, as well as to theprovision of pharmaceuticals containing such a compound as the activeingredient.

DISCLOSURE OF THE INVENTION

Under the above circumstances, the present inventors carried out carefulstudies, and found that the pyrimidine derivatives represented by thefollowing formula (1) and their salts exhibit excellent endothelinantagonism and thus are useful as medicines--particularly those forcirculatory diseases. The present invention was accomplished based onthis finding.

Accordingly, the present invention provides a pyrimidine derivative ofthe following formula (1) or a salt thereof: ##STR2## [wherein R¹represents a lower alkyl group; each of R² and R³, which are identicalto or different from each other, represents a hydrogen atom, a loweralkyl group, or a lower alkoxyl group; each of R⁴ and R⁵, which areidentical to or different from each other, represents a hydrogen atom ora lower alkyl group; R⁶ represents a lower alkyl group, --OR⁷, or --NR⁸R⁹ ; and n is a number between 0 and 3 inclusive (wherein R⁷ representsa hydrogen atom, a lower alkyl group, a phenyl group which may have asubstituent, or an aralkyl group which may have a substituent; and eachof R⁸ and R⁹, which are identical to or different from each other,represents a hydrogen atom, a hydroxyl group, a lower alkyl group whichmay have a substituent, a lower alkenyl group which may have asubstituent, an aryl group which may have a substituent, an aralkylgroup which may have a substituent, an amino group which may have asubstituent, a heterocyclic group which may have a substituent, aheterocyclic-alkyl group which may have a substituent, or R⁸ and R⁹ maybe linked to each other so as to form a 5- to 7-membered ring along withtheir adjacent nitrogen atom)].

The present invention also provides a medicine containing a pyrimidinederivative of formula (1) or a salt thereof.

The present invention also provides a pharmaceutical compositioncontaining a pyrimidine derivative of formula (1) or a salt thereof anda pharmaceutically acceptable carrier.

The present invention also provides use as a medicine of a pyrimidinederivative of formula (1) or a salt thereof.

The present invention also provides a method for treating diseasesinduced by endothelin, wherein the method is characterized byadministering an effective amount of a pyrimidine derivative of formula(1) or a salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the ET_(A) receptor antagonism of Compound No.92. FIG. 2 is a graph showing the ET_(B) receptor antagonism of CompoundNo. 68.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the term "lower" is used to indicate that thenumber of carbon atoms is between 1 and 6 inclusive.

In the formula (1), the lower alkyl groups represented by R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ include linear, branched, or cyclic alkylgroups having 1-6 carbon atoms, examples of which include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, cyclopropyl, cyclopentyl, and cyclohexyl.

Of the listed groups, R¹ is preferably isopropyl or tert-butyl, withtert-butyl being particularly preferred.

The lower alkoxyl groups represented by R² and R³ include linear,branched, or cyclic alkoxyl groups having 1-6 carbon atoms, examples ofwhich include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

Examples of the phenyl group which may have a substituent and which isrepresented by R⁷ include phenyl groups substituted by C1-C6 alkylgroups, C1-C6 alkoxyl groups, or by halogen atoms. Specific examples ofsuch phenyl groups include methylphenyl, ethylphenyl, isopropylphenyl,methoxyphenyl, ethoxyphenyl, chlorophenyl, bromophenyl, andfluorophenyl.

The aralkyl groups which may have substituents and which are representedby R⁷, R⁸, and R⁹ include phenylalkyl groups, naphthylalkyl groups,biphenylalkyl groups, and indanyl groups. These groups may besubstituted by hydroxy, C1-C6 alkyl, C1-C6 alkoxyl, C1-C3 alkylenedioxy,halogen, nitro, trifluoromethyl, or cyano groups. Examples of the alkylmoieties of the aralkyl groups include C1-6 alkyl groups. The aralkylgroups may be substituted by one to three groups of the above-mentionedsubstituents. These substituents may be substituted at either the arylmoiety or the alkyl moiety of the aralkyl group. Specific examples ofthe aralkyl groups which may have substituents include benzyl,phenethyl, phenylpropyl, naphthylmethyl, naphthylethyl, biphenylmethyl,and indan-1-yl groups, and these groups may be substituted by one tothree groups selected from among the groups consisting of chloro,fluoro, methoxy, ethoxy, methyl, ethyl, nitro, cyano, andtrifluoromethyl groups.

The lower alkyl groups which may have substituents and which arerepresented by R⁸ and R⁹ include, in addition to the lower alkyl groupslisted for R¹ through R⁹ groups, alkyl groups substituted by one tothree halogen atoms, hydroxyl groups, etc.

The lower alkenyl groups which may have substituents include linear,branched, or cyclic alkenyl groups having 2-6 carbon atoms, as well asthe same groups substituted by one to three halogen atoms, hydroxylgroups, etc. Specific examples include vinyl, propenyl, and isobutenylgroups.

Examples of the aryl group may be phenyl or naphtyl which may besubstituted by one to three C1-C6 alkyl groups, C2-C6 alkenyl groups,C1-C6 alkoxyl groups, C1-C6 alkylthio groups, halogen atoms, hydroxygroups, amino groups, nitro groups, alkoxycarbonyl groups or C1-C6haloalkyl groups, etc. Specific examples of the aryl group which mayhave a substituent include phenyl, naphthyl, mono- or di-chlorophenyl,mono- or di-fluorophenyl, mono-, di-, or tri-methoxyphenyl, mono- ordi-methylphenyl, mono- or di-ethylphenyl, mono- or di-isopropylphenyl,tert-butylphenyl, isopropenylphenyl, hydroxyphenyl, nitrophenyl,aminophenyl, ethoxycarbonylphenyl, and methylthiophenyl.

Examples of the amino groups which may have substituents and which arerepresented by R⁸ and R⁹ include arylamino groups, heterocyclic aminogroups, alkylamino groups, and alkenylamino groups. More specifically,mention may be given to phenylamino groups, C1-C6 alkyl-substitutedphenylamino groups, pyridylamino groups, and C1-C6 alkylamino groups.

Examples of the heterocyclic group which may have a substituent or theheterocyclic-alkyl group which may have a substituent include furylgroups, thienyl groups, pyrazolyl groups, thiazolyl groups, thiadiazolylgroups, imidazolyl groups, pyridyl groups, pyrimidinyl groups, pyrazinylgroups, furylalkyl groups, thienylalkyl groups, pyrazolylalkyl groups,thiazolylalkyl groups, imidazolylalkyl groups, pyridylalkyl groups, andpyrimidinylalkyl groups, and these groups may be substituted by C1-C6alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, or halogenatoms. Specific examples include furyl groups, thienyl groups, pyrazolylgroups, thiazolyl groups, pyridyl groups, pyrimidinyl groups, pyrazinylgroups, furfuryl groups, thienylmethyl groups, pyrazolylmethyl groups,thiazolylmethyl groups, imidazolylmethyl groups, pyridylmethyl groups,and pyrimidinylmethyl groups, all of which groups may be substituted bya group selected from among the groups consisting of methyl, ethyl,methoxy, ethoxy, chloro, fluoro, and trifluoromethyl.

Examples of the 5- to 7-membered ring formed by --NR⁸ R⁹ includepyrrolidinyl groups, piperidinyl groups, and perhydroazepinyl groups.

The salts of the compound (1) of the present invention are notparticularly limited so long as they are pharmaceutically acceptable.Examples of the salts include mineral acid salts such as hydrochloricacid salts and sulfuric acid salts; organic acid salts such as aceticacid salts, oxalic acid salts, and citric acid salts; alkali metal saltssuch as sodium salts and potassium salts, alkaline earth metal saltssuch as calcium salts and magnesium salts; and salts of organic basessuch as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) salts.

Also, the compound (1) of the present invention encompasses its hydratesand solvates.

The compound (1) of the present invention may be prepared in accordancewith the following reaction scheme. ##STR3## [wherein R¹, R², R³, R⁴,R⁵, R⁸, R⁹, and n have the same meanings as defined above, R^(7a)represents a lower alkyl group, a substituted or unsubstituted phenylgroup, or a substituted or unsubstituted aralkyl group, and R¹⁰represents a lower alkyl group].

Briefly, a compound (2) is reacted with a hydroxy fatty acid ester##STR4## to obtain a compound (1a). Independently, a compound (2) isreacted with an alcohol ##STR5## to obtain a compound (3), and thethus-obtained compound (3) is oxidized to afford a compound (1b).Compounds (1a) and (1b) are mutually transformable through hydrolysis oresterification. When compound (1b) is reacted with an amine [HNR⁸ R⁹ ],a compound (1c) is obtained. The obtained compound (1c) affords acompound (1d) through a nucleophilic reaction by use of an organic metalreagent.

The compounds (2) and (3) are known compounds and can be obtained by aknown method (see Japanese Patent Application Laid-Open (kokai) No.5-222003). Each step of the above-described reaction scheme will next bedescribed.

Method for Obtaining Compound (1a) From Compound (2):

Compound (2) may be reacted with a hydroxy fatty acid ester without useof any solvent or in a polar solvent such as N,N-dimethylformamide (DMF)or dimethylsulfoxide (DMSO), in the presence of a base such as sodium,sodium hydride, potassium hydride, potassium t-butoxide, or potassiumcarbonate.

Method for Obtaining Compound (1b) From Compound (3):

Compound (3) may be placed in a polar solvent such as DMF, acetone,etc., and oxidized through use of an oxidizer such as chromate typifiedby pyridinium dichromate (PDC) and a Jones reagent, rutheniumchloride-sodium periodide, etc. Method for obtaining compound (1b) fromcompound (1a):

Compound (1a) may be subjected to a conventional hydrolysis using, forexample, an alkali (NaOH, KOH, etc.). Method for obtaining compound (1a)from compound (1b):

Compound (1b) may be esterified by use of the following materials ormethods: (1) use of an acid catalyst (e.g., sulfuric acid, hydrochloricacid, p-toluenesulfonic acid), (2) use of a dehydration-condensing agent(use of a dehydration-condensing agent such as dicyclohexylcarbodiimide(DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) in thepresence or absence of dimethylaminopyridine), (3) a method via an acidchloride by use of thionyl chloride or oxalyl chloride, (4) a method viaan acid anhydride mixture by use of ethyl chlorocarbonate, isobutylchlorocarbonate, etc., and (5) a method in which the alcohol moiety isactivated with thionyl chloride, etc.

Method for Obtaining Compound (1c) From Compound (1b):

Compound (1b) may be amidified by use of the following materials ormethods: (1) use of a dehydration-condensing agent such as DCC or WSC,(2) a method via an active ester (a phenyl ester such as p-nitrophenylester, N-hydroxybenzotriazol ester, N-hydroxysuccinimide ester, etc.)produced by use of the above-mentioned dehydration-condensing agent, (3)a method via an acid chloride by use of thionyl chloride or oxalylchloride, (4) a method via an acid anhydride mixture by use of ethylchlorocarbonate, isobutyl chlorocarbonate, etc., (5) a method in which aWoodward K reagent is used, and (6) a method in which a reagentordinarily used for amidification (such asN-ethyl-2'-hydroxybenzoisoxazolium trifluoroborate,N-ethyl-5-phenylisoxazolium-3'-sulfonate,1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline,benzotriazolyl-N-hydroxytrisdimethylaminophosphonium hexafluorophosphatesalts, and diphenylphosphoryl azide) is used.

Method for Obtaining Compound (1d) From Compound (1c):

Compound (1c) may be alkylated by use of any of the following organicmetallic reagents (a)-(d): (a) organic magnesium reagents, (b) organiclithium reagents, (c) organic copper reagents, and (d) organic zincreagents.

Compound (1b) of the present invention may also be prepared through thefollowing reaction scheme (B) or (C). ##STR6## [wherein R¹, R², R³, R⁴,R⁵, and n have the same meanings as defined above].

Briefly, compound (2) is reacted with alcohol (4) to obtain an ethercompound (5). When the compound (5) is subjected to hydrolysis, acompound (1e) is obtained. After the ester moiety of the compound (1e)is hydrolyzed, a compound (1b) can be obtained. ##STR7## [wherein R¹,R², R³, R⁴, R⁵, and n have the same meanings as defined above].

According to the reaction scheme (C), compound (3) is oxidized to betransformed into an aldehyde (6). When the aldehyde (6) is furtheroxidized, compound (1b) can be obtained.

Typical compounds of formula (1) of the present invention are shown inthe following Tables 1 through 9. In the Tables, Me stands for methyl,Et stands for ethyl, t-Bu stands for tert-butyl, i-Pr stands forisopropyl, n-Pen stands for n-pentyl, n-Hex stands for n-hexyl, Phstands for phenyl, and Bn stands for benzyl.

                                      TABLE 1                                     __________________________________________________________________________     ##STR8##                                                                     Compound No.                                                                            n        R.sup.7                                                    __________________________________________________________________________    1         0        Et                                                         2         0        H                                                          3         1        H                                                          4         2        H                                                          5         3        H                                                          6         3        i-Pr                                                       7         1        Bn                                                         8         1        n-Hex                                                      9         1        Et                                                         10        0        Bn                                                         11        2                                                                                       ##STR9##                                                  12        0                                                                                       ##STR10##                                                 66        0        Me                                                         67        2        Me                                                         69        1        i-Pr                                                       108       1        Me                                                         109       1                                                                                       ##STR11##                                                 __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                         ##STR12##                                                                    Compound No.                                                                           R.sup.1 R.sup.2 R.sup.3                                                                             n    R.sup.4                                                                            R.sup.5                                                                            R.sup.7                         ______________________________________                                        110      t-Bu    H       H     1    Me   Me   H                               111      t-Bu    H       H     1    Et   Et   H                               112      t-Bu    H       H     1    H    Me   H                               117      t-Bu    Me      Me    1    H    H    H                               118      t-Bu    EtO     EtO   1    H    H    H                               119      t-Bu    i-PrO   i-PrO 1    H    H    H                               124      i-Pr    H       H     1    H    H    H                               ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                                                    (1c)                                               ##STR13##                                                                    Compound No.                                                                            n      R.sup.8                                                                              R.sup.9                                               ______________________________________                                        13        1      H      H                                                     14        1      H      Bn                                                    15        0      H      Bn                                                    16        2      H      Bn                                                    17        1      H                                                                                     ##STR14##                                            18        1      H      Ph                                                    19        3      H      Bn                                                    20        1      H                                                                                     ##STR15##                                            21        1      H                                                                                     ##STR16##                                            22        1      H                                                                                     ##STR17##                                            23        1      H                                                                                     ##STR18##                                            24        0      H                                                                                     ##STR19##                                            25        2      H      Ph                                                    26        1      H                                                                                     ##STR20##                                            27        1      H                                                                                     ##STR21##                                            28        1      H                                                                                     ##STR22##                                            29        2      H                                                                                     ##STR23##                                            30        2      H                                                                                     ##STR24##                                            31        0      H                                                                                     ##STR25##                                            32        0      H                                                                                     ##STR26##                                            ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                                                    (1c)                                               ##STR27##                                                                    Compound No.                                                                            n      R.sup.8                                                                              R.sup.9                                               ______________________________________                                        33        1      H                                                                                     ##STR28##                                            34        1      H                                                                                     ##STR29##                                            35        0      H      Ph                                                    36        0      H                                                                                     ##STR30##                                            37        2      H                                                                                     ##STR31##                                            38        2      H                                                                                     ##STR32##                                            39        0      H      OH                                                    40        3      H                                                                                     ##STR33##                                            41        3      H                                                                                     ##STR34##                                            42        1      H                                                                                     ##STR35##                                            43        1      H      n-Pen                                                 44        3      H                                                                                     ##STR36##                                            45        1      (CH.sub.2).sub.6                                             46        3      H                                                                                     ##STR37##                                            47        3      H                                                                                     ##STR38##                                            48        1      H                                                                                     ##STR39##                                            49        1      H      Et                                                    50        1      H                                                                                     ##STR40##                                            51        1      H                                                                                     ##STR41##                                            52        2      H                                                                                     ##STR42##                                            ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                                                    (1c)                                               ##STR43##                                                                    Compound No.                                                                           n     R.sup.8       R.sup.9                                          ______________________________________                                        53       1     H                                                                                            ##STR44##                                       54       0                                                                                    ##STR45##                                                                                   ##STR46##                                       55       1     H                                                                                            ##STR47##                                       56       1     H                                                                                            ##STR48##                                       57       1     H                                                                                            ##STR49##                                       58       1     Me                                                                                           ##STR50##                                       59       1     Me                                                                                           ##STR51##                                       60       1     H                                                                                            ##STR52##                                       61       1     H                                                                                            ##STR53##                                       62       0     H                                                                                            ##STR54##                                       63       0     H                                                                                            ##STR55##                                       64       1     H                                                                                            ##STR56##                                       65       1     H                                                                                            ##STR57##                                       68       1     H                                                                                            ##STR58##                                       70       1     H                                                                                            ##STR59##                                       71       1     H                                                                                            ##STR60##                                       72       1     H                                                                                            ##STR61##                                       ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                                                    (1c)                                               ##STR62##                                                                    Compound No.                                                                             n       R.sup.8                                                                             R.sup.9                                              ______________________________________                                        73         1       H                                                                                    ##STR63##                                           74         1       H                                                                                    ##STR64##                                           75         1       H                                                                                    ##STR65##                                           76         1       H                                                                                    ##STR66##                                           77         1       H     Me                                                   78         1       Me    Me                                                   79         1       H                                                                                    ##STR67##                                           80         1       H                                                                                    ##STR68##                                           81         1       H                                                                                    ##STR69##                                           82         1       H                                                                                    ##STR70##                                           83         1       H                                                                                    ##STR71##                                           84         1       H                                                                                    ##STR72##                                           85         1       H                                                                                    ##STR73##                                           86         1       H                                                                                    ##STR74##                                           87         1       H                                                                                    ##STR75##                                           ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                                                    (1c)                                               ##STR76##                                                                    Compound No.                                                                             n        R.sup.8                                                                             R.sup.9                                             ______________________________________                                        88         1        H                                                                                    ##STR77##                                          89         1        H                                                                                    ##STR78##                                          90         1        H                                                                                    ##STR79##                                          91         1        H                                                                                    ##STR80##                                          92         1        H                                                                                    ##STR81##                                          93         1        H                                                                                    ##STR82##                                          94         1        H                                                                                    ##STR83##                                          95         1        H                                                                                    ##STR84##                                          96         1        H                                                                                    ##STR85##                                          97         0        H                                                                                    ##STR86##                                          98         2        H                                                                                    ##STR87##                                          99         1        H                                                                                    ##STR88##                                          100        1        H                                                                                    ##STR89##                                          ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                                                    (1c)                                               ##STR90##                                                                    Compound No.                                                                             n        R.sup.8                                                                             R.sup.9                                             ______________________________________                                        101        0        H                                                                                    ##STR91##                                          102        1        H                                                                                    ##STR92##                                          103        1        H                                                                                    ##STR93##                                          104        1        H                                                                                    ##STR94##                                          105        1        H                                                                                    ##STR95##                                          106        0        H                                                                                    ##STR96##                                          107        1        H                                                                                    ##STR97##                                          ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                                                    (1c)                                               ##STR98##                                                                    Com-                                                                          pound                                                                         No.    R.sup.1                                                                              R.sup.2                                                                              R.sup.3                                                                            n   R.sup.4                                                                           R.sup.5                                                                           R.sup.8                                                                           R.sup.9                             ______________________________________                                        113    t-Bu   H      H    1   H   Me  H                                                                                  ##STR99##                          114    t-Bu   H      H    1   H   Me  H                                                                                  ##STR100##                         115    i-Pr   H      H    1   H   H   H                                                                                  ##STR101##                         116    i-Pr   H      H    1   H   H   H                                                                                  ##STR102##                         120    t-Bu   Me     Me   1   H   H   H                                                                                  ##STR103##                         121    t-Bu   Me     Me   1   H   H   H                                                                                  ##STR104##                         122    t-Bu   EtO    EtO  1   H   H   H                                                                                  ##STR105##                         123    t-Bu   i-PrO  i-PrO                                                                              1   H   H   H                                                                                  ##STR106##                         ______________________________________                                    

The pyrimidine derivative (1) of the present invention or a saltthereof, after being processed together with a pharmaceuticallyacceptable carrier according to a customary method, may be formed intovarious peroral or parenteral pharmaceutical compositions of a solidtype, semi-solid type, or liquid type.

Examples of peroral preparations include tablets, pills, granules, softand hard capsules, powders, fine granules, emulsions, syrups, pellets,and elixirs. Examples of parenteral preparations include injections,instillations, transfusions, ointments, lotions, tonics, sprays,suspensions, oils, emulsions, and suppositories. In order to prepare apharmaceutical composition containing the compound of the presentinvention as the active ingredient, known methods may be used, and theremay also be used as required surfactants, excipients, coloring agents,odor improving agents, preservatives, stabilizers, buffers, suspensionbases, isotonic agents, etc.

The amount of administration of the pyrimidine derivative (1) or a saltthereof varies in accordance with the identity of the compound, thedisease which is to be treated or prevented, the manner ofadministration, the age and symptoms of the patient, duration oftreatment, etc. In the case of parenteral administration, the amount ofadministration is preferably between 0.01 and 30 mg/kg for subcutaneous,intravenous, intramuscular, or rectal administration. In contrast, inthe case of peroral administration, the compound is preferablyadministered in an amount of 0.01-100 mg/kg, more preferably 0.5-30mg/kg.

EXAMPLES

The present invention will next be described in more detail by theexamples, which should not be construed as limiting the inventionthereto.

Example 1 (Synthesis of Compound No. 1)

Metallic sodium (160 mg) was added to ethyl glycolate (5 g) and themixture was stirred for 30 minutes at room temperature. To the resultanttransparent solution was added4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide(993 mg), and the mixture was stirred for 5 hours at 95° C. Ethylacetate was added to the reaction mixture, followed by successivewashing with 1N-HCl, water, and saturated brine.

The organic layer was dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform-methanol 30:1), to give 732mg of ethyl[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS) : 1.22(3H, t, J=7.1 Hz), 1.29(9H, s), 4.01(3H,s), 4.18(2H, q, J=7.1 Hz), 5.10(2H, s), 6.89(1H, brt, J=7.8 Hz),7.00(1H, brd, J=7.8 Hz), 7.12(1H, brt, J=7.8 Hz), 7.33(1H, brd, J=7.8Hz), 7.40(1H, t, J=4.6 Hz), 7.41(2H, d, J=8.8 Hz), 8.34(2H, m), 8.97(2H,d, J=4.6 Hz); IR(KBr)cm⁻¹ : 2965, 1755, 1620, 1580, 1560, 1500, 1345,1255, 1175, 1085, 750

Example 2 (Synthesis of Compound No. 2)

1N-NaOH (10 ml) was added to a solution of Compound No. 1(625 mg) inethanol (20 ml). The mixture was stirred overnight at room temperature,then solvent was evaporated under reduced pressure. 1N-HCl (10 ml) wasadded, and the mixture was extracted with chloroform (20 ml), followedby washing successively with water and saturated brine. Drying overanhydrous sodium sulfate and concentrating under reduced pressure gave586 mg of[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]aceticacid as a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.26(9H, s), 4.02(3H, s), 5.40(2H, s),6.92(1H, dt, J=7.9, 1.5 Hz), 7.02(1H, dd, J=7.9, 1.5 Hz), 7.14(1H, dt,J=7.9, 1.5 Hz), 7.34(1H, dd, J=7.9, 1.5 Hz), 7.39(2H, d, J=8.5 Hz),7.43(1H, t, J=4.9 Hz), 8.44(2H, d, J=8.5 Hz), 9.14(2H, d, J=4.9 Hz)

Example 3 (Synthesis of Compound No. 3)

To a solution of4-t-butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide (3.2 g) in dimethylformamide (50 ml) was added pyridiniumdichromate (31.9 g). The mixture was stirred for 12 hours at roomtemperature, and subsequently supplemented with pyridinium dichromate(10.6 g), followed by stirring for 12 hours. Ethyl acetate was added,and the mixture was washed with 1N-HCl and then with water. The organiclayer was extracted with sat. aq. NaHCO₃, and the aqueous layer waswashed with ethyl acetate. The aqueous layer was acidified with diluteHCL, and then extracted with ethyl acetate. The organic layer was washedwith saturated brine. Drying over anhydrous magnesium sulfate andconcentrating under reduced pressure gave 1.85 g of3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionicacid as a pale yellow powder.

¹ H-NMR(CDCl₃ -CD₃ OD(4:1), ppm, TMS) 1.29(9H, s), 2.64(2H, t, J=6.2Hz), 3.91(3H, s), 4.75(2H, t, J=6.2 Hz), 6.84(1H, dt, J=7.9, 1.5 Hz),6.96(1H, brd, J=7.9 Hz), 6.98(1H, dd, J=7.9, 1.5 Hz), 7.09(1H, dt,J=7.9, 1.5 Hz), 7.43(2H, d, J=8.8 Hz), 7.50(1H, t, J=4.9 Hz), 8.31(2H,m), 9.02(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 3400, 2965, 1730, 1620, 1580,1560, 1500, 1340, 1255, 1175, 1080, 750

Example 4 (Synthesis of Compound No. 4)

The procedure described in Example 3 was repeated using4-t-butyl-N-[6-(4-hydroxybutyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide,to obtain4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyricacid as a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.95(2H, m), 2.25(2H, t, J=7.2Hz), 3.90(3H, s), 4.52(2H, t, J=6.1 Hz), 6.84(1H, dt, J=7.7, 1.5 Hz),6.96(1H, dd, J=7.7, 1.5 Hz), 6.97(1H, dd, J=7.7, 1.5 Hz) 7.09(1H, dt,J=7.7, 1.5 Hz), 7.42(2H, d, J=8.6 Hz) 7.45(1H, t, J=4.9 Hz), 8.34(2H,m), 9.06(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 3305, 29 65, 1735, 1685, 1615,1565, 1500, 1335, 1260, 1165, 1115, 1075, 750

Example 5 (Synthesis of Compound No. 5)

The procedure described in Example 3 was repeated using4-t-butyl-N-[6-(5-hydroxypentyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl )-4-pyrimidinyl]benzenesulfonamide, to obtain5-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenox)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanoicacid as a of yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s) 1.57(2H, m), 1.70(2H, m), 2.29(2H,t, J=7.3H z), 3.9(3H, s), 4.49(2H, t, J=6.2 Hz), 6.83(1H, dt, J=7.8, 1.5Hz), 6.95(1H, dd, J=7.8 1.5 Hz), 7.00(1H, brd, J=7.8 Hz), 7.08(1H, dt,J=7.8, 1.5 Hz), 7.43(2H, d, J=8.6 Hz), 7.46(1H, t, J=4.9 Hz), 8.33(2H,brd, J=8.6 Hz), 9.08(2H, d, J=4.9 Hz)

Example 6 (Synthesis of Compound No. 6)

Concentrated sulfuric acid (2 droplets) was added to a solution ofCompound No. 5(41.3 mg) in isopropyl alcohol (2 ml). The mixture wasstirred overnight at room temperature, then solvent was evaporated underreduced pressure. The residue was dissolved in ethyl acetate, and themixture was washed successively with sat. ag. NaHCO₃, water, 1N-HCl, andsaturated brine. Drying over anhydrous sodium sulfate and concentratingunder reduced pressure gave 34.9 mg of isopropyl5-[6-(4-t-butylphenyl-sulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanoateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.19(6H, d, J=6.1 Hz), 1.29(9H, s), 1.53(2H,m), 1.66(2H, m), 2.19(2H, t, J=7.3 Hz), 3.91(3H, s), 4.48(2H, t, J=6.1Hz), 4.97(1H, sep, J=6.1 Hz), 6.83(1H, dt, J=7.8, 1.5 Hz), 6.96(1H, dd,J=7.8, 1.5 Hz), 6.98(1H, brd, J=7.8 Hz), 7.08(1H, dt, J=7.8, 1.5 Hz),7.42(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.6 Hz), 8.32(2H, m), 9.02(2H, d,J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1725, 1620, 1580, 1560, 1500, 1340, 1255,1170, 1080, 750

Example 7 (Synthesis of Compound No. 7)

The procedure described in Example 6 was repeated using Compound No. 3and benzyl alcohol, to obtain benzyl3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.72(2H, t, J=6.1 Hz), 3.90(3H,s), 4.80(2H, t, J=6.1 Hz), 5.03(2H, s), 6.79(1H, dt, J=7.7, 1.5 Hz),6.93(1H, dd, J=7.7, 1.5 Hz), 6.99(1H, brd, J=7.7 Hz), 7.06(1H, dt,J=7.7, 1.5 Hz), 7.28(5H, m), 7.41(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.6Hz), 8.35(2H, m), 9.00(2H, d, J=4.9 Hz)

Example 8 (Synthesis of Compound No. 8)

The procedure described in Example 6 was repeated using Compound No. 3and n-hexyl alcohol, to obtain n-hexyl3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 0.85(3H, t, J=6.8 Hz), 1.25(6H, m), 1.29(9H,s), 1.54(2H, m), 2.68(2H, t, J=6.2 Hz), 3.93(3H, s), 4.00(2H, t, J=6.7Hz), 4.78(2H, t, J=6.2 Hz), 6.78˜7.18(4H, m), 7.41(2H, d, J=8.6 Hz),7.42(1H, t, J=4.9 Hz), 8.34(2H, m), 9.01(2H, d, J=4.9 Hz)

Example 9 (Synthesis of Compound No. 9)

The procedure described in Example 6 was repeated using Compound No. 3and ethanol, to obtain ethyl3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.18(3H, t, J=7.2 Hz), 1.29(9H, s), 2.67(2H,t, J=6.2 Hz), 3.94(3H, s), 4.06(2H, q, J=7.2 Hz), 4.78(2H, t, J=6.2 Hz),6.77˜7.18(4H, m), 7.42(2H, d, J=8.5 Hz), 7.42(1H, t, J=4.9 Hz), 8.35(2H,m), 9.00(2H, d, J=4.9 Hz)

Example 10 (Synthesis of Compound No. 10)

The procedure described in Example 6 was repeated using Compound No. 2and benzyl alcohol, to obtain benzyl[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s) 3.98(3H, s), 5.15(2H, s), 5.17(2H,s), 6.78(1H, dt, J=7.7, 1.5 Hz), 6.98(1H, dd, J=7.7, 1.5 Hz), 7.09(1H,dt, J=7.7, 1.5 Hz), 7.24(6H, m), 7.41(1H, t, J=4.9 Hz), 7.42(2H, d,J=8.5 Hz), 8.35(2H, m), 8.98(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1755,1620, 1580, 1560, 1500, 1345, 1255, 1175, 1085, 750

Example 11 (Synthesis of Compound No. 11)

The procedure described in Example 6 was repeated using Compound No. 4and 4-methoxybenzyl alcohol, to obtain 4-methoxybenzyl4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyrateas a pale yellow oil.

¹ H-NMR(CDCl₃ , ppm, TMS): 1.29(9H, s), 1.93(2H, m), 2.17(2H, t, J=7.6Hz), 3.80(3H, s), 3.85(3H, s), 4.48(2H, t, J=6.0 Hz), 5.00(2H, s),6.77(1H, dt, J=7.7, 1.5 Hz), 6.87(2H, d, J=7˜8.5 Hz), 6.83˜6.97(2H, m),7.02(1H, dt, J=7.7, 1.5 Hz), 7.26(2H, d, J=8.5 Hz), 7.42(1H, t, J=4.9Hz), 7.42(2H, d, J=8.5 Hz), 8.35(2H, m), 9.01(2H, d, J=4.9 Hz)IR(KBr)cm⁻¹ : 2965, 1730, 1615, 1580, 1560, 1500, 1340, 1250, 1170,1080, 750

Example 12 (Synthesis of Compound No. 12)

To a solution of Compound No. 2(40 mg) inmethylenechloride-dimethylformamide (3:1, 2 ml) were added3-chlorophenol (45 ml), N,N-dimethylaminopyridine (1 mg), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (16.3 mg), and themixture was stirred overnight at room temperature. Solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate. The solution was successively washed with sat. aq.NaHCO₃, water, 1N-HCl, and saturated brine. The residue resulting fromdrying over anhydrous sodium sulfate and concentrating under reducedpressure was purified by preparative thin-layer chromatography (byMerck; eluent: chloroform-methanol (10:1)). The purified material wasdissolved in ethyl acetate, and the solution was washed with 1N-HCl andsaturated brine, then brought to dryness over anhydrous sodium sulfate.When the solvent was evaporated under reduced pressure, there wasobtained 3-chlorophenyl[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.98(3H, s), 5.26(2H, s),6.84(1H, dt, J=7.8, 1.5 Hz), 6.95˜7.04(2H, m), 7.10(1H, d, J=7.8, 1.5Hz), 7.15˜7.30(4H, m), 7.43(2H, d, J=8.6 Hz), 7.45(1H, t, J=4.9 Hz),8.36(2H, m), 9.03(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1780, 1620, 1580,1560, 1500, 1340, 1255, 1175, 1085, 750

Example 13 (Synthesis of Compound No. 13)

To a solution of Compound No. 3(21.8 mg) in dimethylformamide (0.5 ml)were added N-hydroxybenzotriazole ammonium salt (6.4 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (8.0 mg), and themixture was stirred for 2.5 hours at room temperature. Ethyl acetate (10ml) was added to the reaction mixture, followed by washing successivelywith 1N-HCl, water, sat. aq. NaHCO₃, water, and saturated brine, anddrying over anhydrous sodium sulfate. Solvent was evaporated underreduced pressure, and the residue was purified by preparative thin-layerchromatography (eluent:chloroform-methanol (5:1)). The purified materialwas dissolved in ethyl acetate, and the resultant solution was washedwith 1N-HCl and saturated brine, then brought to dryness over anhydroussodium sulfate. When the solvent was evaporated under reduced pressure,there was obtained3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide(5.8 mg) as a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.60(2H, t, J=6.5 Hz), 3.93(3H,s), 4.76(2H, t, J=6.5 Hz), 6.80˜7.17(4H, m), 7.44(2H, d, J=8.8 Hz),7.48(1H, t, J=4.9 Hz), 8.36(2H, m), 9.01(2H, d, J=4.9 Hz)

Example 14 (Synthesis of Compound No. 14)

To a solution of Compound No. 3(100 mg) in 1:1dimethylformamide-methylene chloride (8 ml) were addedN-hydroxybenzotriazole.H₂ O (53.8 mg), benzylamine (95.9 mg), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (40 mg), and themixture was stirred overnight at room temperature. Solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate (20 ml). The resultant solution was successively washedwith sat. aq. NaHCO3, water, 1N-HCl, and saturated brine, and dried overanhydrous sodium sulfate. When the residue was concentrated underreduced pressure, there was obtainedN-benzyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-propionamide(100.9 mg) as a oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.67(2H, t, J=6.5 Hz), 3.90(3H,s), 4.39(2H, d, J=5.9 Hz), 4.82(2H, t, J=6.5 Hz), 6.75(1H, m), 6.81(1H,dt, J=7.8, 1.5 Hz), 6.94(1H, dd, J=7.8, 1.5 Hz), 6.97(1H, brd, J=7.8Hz), 7.08(1H, dt, J=7.8, 1.5 Hz), 7.14˜7.25(5H, m), 7.36(1H, t, J=4.9Hz), 7.42(2H, d, J=8.6 Hz), 8.35(2H, m), 8.87(2H, d, J=4.9 Hz)

Example 15 (Synthesis of Compound No. 15)

The procedure described in Example 14 was repeated using Compound No. 2and benzylamine, to obtainN-benzyl-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.68(3H, s), 4.29(2H, d, J=6.1Hz), 5.02(2H, s), 6.20(1H, m), 6.69(1H, dt, J=7.8, 1.5 Hz), 6.78(1H, dd,J=7.8, 1.5 Hz), 6.90(1H, brd, J=7.8 Hz), 6.97(1H, dt, J=7.8, 1.5 Hz),7.05˜7.33(5H, m), 7.43(1H, t, J=4.9 Hz), 7.44(2H, d, J=8.5 Hz), 8.38(2H,m), 8.98(2H, d, J=4.9 Hz)

Example 16 (Synthesis of Compound No. 16)

The procedure described in Example 14 was repeated using Compound No. 4and benzylamine, to obtainN-benzyl-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.01(4H, m), 3.82(3H, s),4.35(2H, d, J=5.6 Hz), 4.49(2H, m), 5.85(1H, m), 6.74(1H, dt, J=7.7, 1.5Hz) 6.81˜6.90(2H, m), 6.96(1H, dt, J=7.7, 1.5 Hz), 7.16˜7.32(5H, m),7.40(1H, t, J=4.9 Hz), 7.43(2H, d, J=8.5 Hz), 8.35(2H, m), 8.96(2H, d,J=4.9 Hz)

Example 17 (Synthesis of Compound No. 19)

The procedure described in Example 14 was repeated using Compound No. 5and benzylamine, to obtainN-benzyl-5-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.52˜1.76(4H, m), 2.22(2H, t,J=7.0 Hz), 3.89(3H, s), 4.35(2H, d, J=5.9 Hz), 4.53(2H, t, J=5.9 Hz),6.36(1H, m), 6.79(1H, t, J=7.6 Hz), 6.88˜6.98(2H, m), 7.04(1H, t, J=7.7Hz), 7.12˜7.29(5H, m), 7.37(1H, t, J=4.6 Hz), 7.43(2H, d, J=8.6 Hz),8.36(2H, m), 8.92(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ : 2965, 1650, 1620, 1580,1560, 1500, 1340.1255, 1175, 1080, 750

Example 18 (Synthesis of Compound No. 24)

The procedure described in Example 14 was repeated using Compound No. 2and phenethylamine, to obtainN-phenethyl-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.65(2H, t, J=7.1 Hz), 3.32(2H,m), 3.81(3H, s), 4.96(2H, s), 5.98(1H, m), 6.75(1H, dt, J=7.8, 1.5 Hz),6.79(1H, dd, J=7.8.1.5 Hz), 6.93(1H, dd, J=7.8.1.5 Hz), 7.01˜7.20(6H,m), 7.45(1H, t, J=4.9 Hz), 7.45(2H, d, J=8.6 Hz), 8.37(2H, m), 9.01(2H,d, J=4.9 Hz)

Example 19 (Synthesis of Compound No. 25)

The procedure described in Example 14 was repeated using Compound No. 4and aniline, to obtainN-phenyl-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.06(2H, m), 2.20(2H, m),3.90(3H, s), 4.53(2H, t, J=5.6 Hz), 6.80˜7.31(6H, m), 7.34˜7.48(5H, m)7.63(1H, m), 8.37(2H, m), 8.94(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 2965,1670, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1080, 775

Example 20 (Synthesis of Compound No. 29)

The procedure described in Example 14 was repeated using Compound No. 4and 2-methoxyaniline, to obtainN-(2-methoxyphenyl)-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.04(2H, m), 2.13(2H, m),3.85(3H, s), 3.88(3H, s), 4.55(2H, t, J=5.6 Hz), 6.81˜7.01(6H, m),7.02(1H, dt, J=7.7, 1.5 Hz), 7.11(1H, dt, J=7.7, 1.5 Hz), 7.41(1H, t,J=4.9 Hz), 7.43(2H, d, J=8.8 Hz), 8.31(2H, m), 8.99(2H, d, J=4.9 Hz)

Example 21 (Synthesis of Compound No. 30)

The procedure described in Example 14 was repeated using Compound No. 4and 3-chloroaniline, to obtainN-(3-chlorophenyl)-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramideas a colorless powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.06(2H, m), 2.23(2H, t, J=7.1Hz), 3.90(3H, s), 4.55(2H, t, J=5.6 Hz), 6.86(1H, dt, J=7.8, 1.5 Hz),6.95(1H, dd, J=7.8, 1.5 Hz), 6.98(1H, dd, J=7.8, 1.5 Hz), 7.04(1H, m),7.11(1H, dt, J=7.8, 1.5 Hz), 7.17(1H, t, J=8.1 Hz), 7.28(1H, m),7.41(1H, t, J=4.9 Hz), 7.43(2H, d, J=8.8 Hz), 7.55(1H, brs), 8.33(2H,m), 8.95(2H, d, J=4.9 Hz)

Example 22 (Synthesis of Compound No. 31)

The procedure described in Example 14 was repeated using Compound No. 2and 2-methoxyaniline, to obtainN-(2-methoxyphenyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a colorless powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.58(3H, s), 3.99(3H, s),5.20(2H, s), 7.30˜7.67(7H, m), 7.36˜7.48(3H, m), 8.26(1H, dd, J=8.1, 1.5Hz), 8.37(2H, m), 8.69(1H, brs), 9.00(2H, d, J=4.6 Hz); IR(KBr)cm⁻¹ :2965, 1695, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 23 (Synthesis of Compound No. 32)

The procedure described in Example 14 was repeated using Compound No. 2and 3-chloroaniline, to obtainN-(3-chlorophenyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a colorless powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.90(3H, s), 5.09(2H, s),6.88(1H, dt, J=7.7, 1.5 Hz), 6.95˜7.10(3H, m), 7.14(1H, dt, J=7.7, 1.5Hz), 7.19(1H, t, J=7.9 Hz), 7.32(1H, t, J=1.8 Hz), 7.37(2H, m), 7.44(2H,d, J=8.8 Hz), 7.48(1H, t, J=4.9 Hz), 8.35(2H, m), 9.04(2H, d, J=4.9 Hz)

Example 24 (Synthesis of Compound No. 35)

The procedure described in Example 14 was repeated using Compound No. 2and aniline, to obtainN-phenyl-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.86(3H, s), 5.11(2H, s),6.85(1H, dt, J=7.7, 1.5 Hz), 6.98(1H, dd, J=7.7, 1.5 Hz), 7.01(1H, brd,J=7.7 Hz), 7.05˜7.14(2H, m), 7.22˜7.38(4H, m), 7.43(2H, d, J=8.5 Hz),7.45(1H, t, J=4.9 Hz), 8.38(2H, m), 9.01(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ :2965, 1700, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 775

Example 25 (Synthesis of Compound No. 36)

The procedure described in Example 14 was repeated using Compound No. 2and 1-naphthalenemethylamine, to obtainN-(1-naphthylmethyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.58(3H, s), 4.78(2H, d, J=5.6Hz), 5.05(2H, s), 6.30(1H, m), 6.42(1H, dt, J=7.8, 1.5 Hz), 6.56(1H, dd,J=7.8, 1.5 Hz), 6.72(2H, m), 7.26(1H, m), 7.35˜7.50(6H, m),7.78˜7.88(3H, m), 8.34(2H, m), 8.94(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965,1675, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 26 (Synthesis of Compound No. 37)

The procedure described in Example 14 was repeated using Compound No. 4and 3-methoxybenzylamine, to obtainN-(3-methoxybenzyl)-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.01(4H, m), 3.74(3H, s),3.83(3H, s), 4.33(2H, d, J=5.6 Hz), 4.49(2H, m), 5.88(1H, m),6.70˜6.81(5H, m), 6.87(1H, dd, J=7.8, 1.5 Hz), 6.98(1H, dt, J=7.8, 1.5Hz), 7.18(1H, dt, J=7.8, 1.5 Hz), 7.41(1H, t, J=4.9 Hz), 7.43(2H, d,J=8.8 Hz), 8.33(2H, m), 8.94(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 2965.1655,1615, 1580, 1560, 1500, 1340, 1260, 1170, 1080, 750

Example 27 (Synthesis of Compound No. 38)

The procedure described in Example 14 was repeated using Compound No. 4and 2-chlorophenethylamine, to obtainN-(2-chlorophenethyl)-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butylamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.95(4H, m), 2.90(2H, t, J=7.0Hz), 3.46(2H, m), 3.87(3H, s), 4.45(2H, m) 5.62(1H, m) 6.76(2H, dt,J=7.8. 1.5 Hz), 6.87(1H, dd, J=7.8, 1.5 Hz), 6.91(1H, dd, J=7.8, 1.5Hz), 6.99(1H, dt, J=7.8, 1.5 Hz), 7.05˜7.19(3H, m), 7.30(1H, m),7.43(1H, t, J=4.9 Hz), 7.43(2H, d, J=8.8 Hz), 8.33(2H, m), 9.00(2H, d,J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1655, 1620, 1580, 1560, 1500, 1340, 1255,1175, 1080, 775

Example 28 (Synthesis of Compound No. 40)

The procedure described in Example 14 was repeated using Compound No. 5and 2-methoxybenzylamine, to obtainN-(2-methoxybenzyl)-5-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.56(2H, m), 1.65(2H, m,),2.15(2H, t, J=7.2 Hz), 3.75(3H, s), 3.88(3H, s), 4.38(2H, d, J=5.6 Hz),4.50(2H, t, J=6.1 Hz), 6.30(1H, m), 6.73˜6.97(5H, m), 7.03(5H, dt, J=7.81.5 Hz), 7.15˜7.24(2H, m), 7.39(1H, t, J=4.9 Hz), 7.43(2H, d, J=8.6 Hz),8.32(2H, m), 8.96(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 2960, 1650, 1620,1580, 1560, 1500.1340, 1245, 1175, 1080, 775

Example 29 (Synthesis of Compound No. 41)

The procedure described in Example 14 was repeated using Compound No. 5and 3-chlorobenzylamine, to obtainN-(3-chlorobenzyl)-5-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.69(4H, m), 2.24(2H, t, J=6.6Hz) 3.90(3H, s), 4.32(2H, d, J=5.9 Hz), 4.54(2H, t, J=6.0 Hz), 6.51(1H,m), 6.80(1H, brt, J=8.3 Hz), 6.94(2H, m), 7.00˜7.20(5H, m), 7.39(1H, t,J=4.9 Hz), 7.43(2H, d, J=8.8 Hz), 8.32(2H, m), 8.93(2H, d, J=4.9 Hz)

Example 30 (Synthesis of Compound No. 51)

The procedure described in Example 14 was repeated using Compound No. 3and 2-methylbenzylamine, to obtainN-(2-methylbenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.24(3H, s), 2.67(2H, t, J=6.4Hz), 3.90(3H, s), 4.37(2H, d, J=5.6 Hz), 4.82(2H, t, J=6.4 Hz), 6.52(1H,m), 6.80(1H, t, J=7.8 Hz), 6.94(1H, d, J=7.8 Hz), 6.96˜7.18(6H, m),7.34(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.7 Hz), 8.37(2H, m), 8.82(2H, d,J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1655, 1620, 1580, 1560, 1500, 1340, 1255,1175, 1080, 750

Example 31 (Synthesis of Compound No. 52)

The procedure described in Example 14 was repeated using Compound No. 4and phenethylamine, to obtainN-phenethyl-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.91(4H, m), 2.75(2H, t, J=6.5Hz), 346(2H, m), 3.86(3H, s), 4.43(2H, m), 5.52(1H, m), 6.72(1H, dt,J=7.8, 1.5 Hz), 6.84(1H, d, J=7.8 Hz), 6.88(1H, dd, J=7.8, 1.5 Hz),6.95(1H, dt, J=7.8, 1.5 Hz), 7.10˜7.30(5H, s) 7.42(1H, t, J=4.9 Hz),7.43(2H, d, J=8.5 Hz), 8.36(2H, m), 8.99(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ :2965, 1655, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1080, 750

Example 32 (Synthesis of Compound No. 44)

The procedure described in Example 14 was repeated using Compound No. 5and 2-chlorophenethylamine, to obtainN-(2-chlorophenethyl)-5-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.52˜1.70(4H, m), 2.13(2H, t,J=7.1 Hz), 2.90(2H, t, J=7.0 Hz), 3.48(2H, m), 3.92(3H, s), 4.50(2H, t,J=6.0 Hz), 6.05(1H, m), 6.81(1H, t, J=8.0 Hz), 6.90˜7.26(7H, m),7.42(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.5 Hz), 8.35(2H, m), 8.95(2H, d,J=4.9 Hz) IR(KBr)cm⁻¹ : 2960, 1650, 1580, 1560, 1500, 1340, 1255, 1170,1080,

Example 33 (Synthesis of Compound No. 46)

The procedure described in Example 14 was repeated using Compound No. 5and phenethylamine, to obtainN-phenethyl-5-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS) 1.29(9H, s), 1.52˜1.67(4H, m), 2.11(2H, t,J=7.7 Hz), 2.76(2H, t, J=7.0 Hz), 3.45(2H, q, J=6.6 Hz), 3.91(3H, s),4.49(2H, t, J=6.1 Hz), 5.91(1H, m), 6.80(1H, dt, J=7.0, 1.5H)6.90˜7.26(8H, m), 7.42(2H, d, J=8.6 Hz), 7.43(1H, t, J=4.6 Hz),8.29˜8.40(2H, m), 8.94(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ : 2960.1650, 1580,1560, 1500, 1340, 1255, 1170, 1080, 750

Example 34 (Synthesis of Compound No. 17)

To a solution of Compound No. 3(51 mg) in 2:1dimethylformamide-methylene chloride (1.5 ml) were addedN-hydroxybenzotriazole.H₂ O (27 mg), 4-methoxybenzylamine (57.5 μl), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (17 mg), and themixture was stirred overnight at room temperature. Solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate (15 ml). The resultant solution was successively washedwith 1N-HCl, water, sat. aq. NaHCO₃, and saturated brine, and dried overanhydrous sodium sulfate. When the residue was concentrated underreduced pressure, there was obtained a sodium salt ofN-(4-methoxybenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a colorless powder (38 mg).

Melting point: 129-131° C. IR(KBr)cm⁻¹ : 2965, 1655, 1615, 1560, 1500,1380, 1250, 1180, 1135, 1080, 750

Example 35 (Synthesis of Compound No. 18)

The procedure described in Example 34 was repeated using Compound No. 3and aniline, to obtain a sodium salt ofN-phenyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

Melting point: 162-163° C. IR(KBr)cm⁻¹ : 2965, 1670, 1600, 1560, 1500,1380, 1250, 1135, 1080, 755

Example 36 (Synthesis of Compound No. 20)

The procedure described in Example 34 was repeated using Compound No. 3and 3,4-methylenedioxybenzylamine, to obtain a sodium salt ofN-(3,4-methylenedioxybenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a colorless powder.

Melting point: 142-145° C. IR(KBr)cm⁻¹ : 2965, 1655, 1560, 1500, 1380,1250, 1180, 1080, 750

Example 37 (Synthesis of Compound No. 21)

The procedure described in Example 34 was repeated using Compound No. 3and 4-chlorobenzylamine, to obtain a sodium salt ofN-(4-chlorobenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a colorless powder.

Melting point: 161-163° C. IR(KBr)cm⁻¹ : 2965, 1655, 1560.1500, 1360,1250, 1180, 1080, 750

Example 38 (Synthesis of Compound No. 22)

The procedure described in Example 34 was repeated using Compound No. 3and 2-chlorophenethylamine, to obtain a sodium salt ofN-(2-chlorophenethyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a colorless powder.

Melting point: 148-149° C. IR(KBr)cm⁻¹ : 2965, 1655, 1560, 1500, 1365,1250, 1180, 1080, 775

Example 39 (Synthesis of Compound No. 23)

The procedure described in Example 34 was repeated using Compound No. 3and 4-methoxyphenethylamine, to obtain a sodium salt ofN-(4-methoxyphenethyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

Melting point: 140-142° C. IR(KBr)cm⁻¹ : 2965, 1650, 1560, 1500, 1365,1250, 1180, 1080, 750

Example 40 (Synthesis of Compound No. 26)

The procedure described in Example 34 was repeated using Compound No. 3and 3-methoxyaniline, to obtain a sodium salt ofN-(methoxyphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-propionamideas a colorless powder.

Melting point: 160-161° C. IR(KBr)cm⁻¹ : 2965.1670, 1600, 1560, 1500,1380, 1250, 1180, 1080, 750

Example 41 (Synthesis of Compound No. 27)

The procedure described in Example 34 was repeated using Compound No. 3and phenethylamine, to obtain a sodium salt ofN-phenethyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

Melting point: 149-150° C. IR(KBr)cm⁻¹ : 2965, 1655, 1560, 1500, 1365,1250, 1180, 1080, 750

Example 42 (Synthesis of Compound No. 28)

The procedure described in Example 34 was repeated using Compound No. 3and 4-chloroaniline, to obtain a sodium salt ofN-(4-chlorophenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

Melting point: 165-168° C. IR(KBr)cm⁻¹ : 2965, 1675, 1595, 1560, 1500,1380, 1250, 1180, 1080, 750

Example 43 (Synthesis of Compound No. 33)

The procedure described in Example 34 was repeated using Compound No. 3and 3,4,5-trimethoxybenzylamine, to obtain a sodium salt ofN-(3,4,5-trimethoxybenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

Melting point: 142-145° C. IR(KBr)cm⁻¹ : 2965, 1655, 1590, 1580, 1560,1500, 1330, 1250, 1180, 1080, 750

Example 44 (Synthesis of Compound No. 34)

The procedure described in Example 34 was repeated using Compound No. 3and 2-methoxybenzylamine, to obtain a sodium salt ofN-(2-methoxybenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a colorless powder.

Melting point: 138-139° C. IR(KBr)cm⁻¹ : 2965, 1655, 1580, 1560, 1500,1360, 1250, 1175, 1080, 755

Example 45 (Synthesis of Compound No. 42)

The procedure described in Example 34 was repeated using Compound No. 3and cyclohexylamine, to obtain a sodium salt ofN-cyclohexyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-propionamideas a pale yellow powder.

Melting point: 162-164° C. IR(KBr)cm⁻¹ : 2935, 1650, 1560, 1500, 1365,1250, 1180, 1080, 750

Example 46 (Synthesis of Compound No. 43)

The procedure described in Example 34 was repeated using Compound No. 3and n-pentylamine, to obtain a sodium salt ofN-(n-pentyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

Melting point: 142-144° C. IR(KBr)cm⁻¹ : 2960, 1655, 1560, 1365, 1250,1180, 1080, 750

Example 47 (Synthesis of Compound No. 47)

The procedure described in Example 34 was repeated using Compound No. 5and 3-phenyl-1-propylamine, to obtain a sodium salt ofN-(3-phenyl-1-propyl)-5-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]pentanamideas a pale yellow powder.

Melting point: 118-120° C.

Example 48 (Synthesis of Compound No. 48)

The procedure described in Example 34 was repeated using Compound No. 3and 2-methoxyaniline, to obtain a sodium salt ofN-(2-methoxyphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

Melting point: 120-122° C. IR(KBr)cm⁻¹ : 2965, 1675, 1600.1560, 1500,1255, 1135, 1080, 750

The resultant sodium salt was transformed into a free form by acustomary method. The NMR data of the free compound are shown below.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.77(2H, t, J=5.9 Hz), 3.74(3H,s), 3.87(3H, s), 4.89(2H, t, J=5.9 Hz), 6.59(1H, t, J=7.2 Hz),6.77˜7.09(6H, m), 7.40(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.5 Hz), 7.90(1H,brs), 8.29(1H, d, J=7.3 Hz), 8.38(2H, d, J=8.5 Hz), 8.82(1H, brs8.99(2H, d, J=4.9 Hz)

Example 49 (Synthesis of Compound No. 49)

The procedure described in Example 34 was repeated using Compound No. 3,N-methylmorpholine, and an equivalent amount of ethylamine.HCl, toobtain a sodium salt ofN-ethyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a colorless powder.

Melting point: 117-120° C.

Example 50 (Synthesis of Compound No. 39)

To a solution of Compound No. 2(57.6 mg) in 1:1dimethylformamide-methylene chloride (2 ml) were addedN-hydroxybenzotriazole-H₂ O (30.6 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (21.1 mg), and themixture was stirred for 1 hour. Subsequently, hydroxylamine.HCl (39.8mg) and triethylamine (0.08 ml) were added, and the mixture was stirredovernight at room temperature. Solvent was evaporated under reducedpressure, and the residue was dissolved in ethyl acetate (5 ml). Theresultant solution was successively washed with 1N-HCl, water, sat. aq.NaHCO₃, and saturated brine, and dried over anhydrous sodium sulfate.The residue was concentrated under reduced pressure, and subjected topreparative thin-layer chromatography for purification by use ofchloroformmethanol (10:1) as an eluent. The purified material wasdissolved in ethyl acetate , and the resultant solution was successivelywashed with 1N HCl and brine, and dried over anhydrous magnesiumsulfate. When solvent was evaporated, there was obtainedN-hydroxy-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a colorless powder (12 mg).

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 4.00(3H, s), 5.14(2H, s),6.89(1H, t, J=7.6 Hz), 7.00(1H, d, J=7.6 Hz), 7.12(1H, t, J=7.6 Hz),7.32(1H, d, J=7.6 Hz), 7.40(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.3 Hz),8.37(2H, m), 8.99(2H, d, J=4.9 Hz)

Example 51 (Synthesis of Compound No. 45)

The procedure described in Example 14 was repeated using Compound No. 3and homopiperidine, to obtainhomopiperidino-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.28(9H, s), 1.49(4H, m), 1.64(4H, m),2.72(2H, t, J=6.7 Hz), 3.36(2H, t, J=6.1 Hz), 3.46(2H, t, J=6.1 Hz),3.96(3H, s), 4.88(2H, t, J=6.7 Hz), 6.82(1H, t, J=8.1 Hz), 6.92˜7.14(3H,m), 7.40(1H, t, J=4.9 Hz), 7.40(2H, d, J=8.6 Hz), 8.32(2H, m), 9.00(2H,d, J=4.9 Hz)

Example 52 (Synthesis of Compound No. 50)

The procedure described in Example 14 was repeated using Compound No. 3and 3-methylaniline, to obtainN-(3-methylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.29(3H, s), 2.74(2H, t, J=6.2Hz), 3.86(3H, s), 4.85(2H, t, J=6.2 Hz), 6.70(1H, dt, J=7.8, 1.5 Hz),6.85˜7.30(7H, m), 7.40(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.8 Hz), 8.36(2H,m), 8.93(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1685, 1615, 1580, 1560,1500, 1340, 1255, 1175, 1085, 750

Example 53 (Synthesis of Compound No. 53)

The procedure described in Example 14 was repeated using Compound No. 3and 2-isopropylaniline, to obtainN-(2-isopropylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.06(6H, d, J=6.8 Hz), 1.29(9H, s), 2.86(2H,t, J=6.5 Hz), 3.03(1H, sep, J=6.8 Hz), 3.92(3H, s), 4.92(2H, t, J=6.5Hz), 6.80(1H, t, J=7.7 Hz), 6.95(1H, d, J=7.1 Hz), 6.99˜7.32(6H, m),7.36(1H, d, J=8.1 Hz), 7.43(2H, d, J=8.6 Hz), 8.43(2H, d, J=8.6 Hz),8.59(2H, d, J=4.9 Hz), 8.86(1H, brs)

Example 54 (Synthesis of Compound No. 88)

Oxalyl chloride (9.5 mg) was added to a solution of Compound No. 3(40.2mg) in methylene chloride (0.3 ml). One droplet of dimethylformamide wasadded thereto, and the resulting mixture was stirred at room temperaturefor 30 minutes. Subsequently,2-amino-5-trifluoromethyl-1,3,4-thiadiazole (24.1 mg) was added, and themixture was stirred overnight at room temperature. Ethyl acetate (10 ml)was added to the reaction mixture, followed by washing successively withsat. aq. NaHCO₃, water, 1N-HCl, water, and saturated brine and dryingover anhydrous sodium sulfate. Solvent was evaporated under reducedpressure, then the residue was purified by preparative thin layerchromatography (eluent:chloroform-methanol (5:1)), dissolved in ethylacetate, washed with 1N-HCl and saturated brine, and dried overanhydrous sodium sulfate. When the solvent was evaporated under reducedpressure, there was obtainedN-(5-trifluoromethyl-1,3,4-thiadiazole-2-yl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder (32.9 mg).

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.12(2H, t, J=6.7 Hz), 3.85(3H,s), 4.83(2H, t, J=6.7 Hz), 6.74(1H, t, J=7.6 Hz), 6.86(1H, d, J=7.6 Hz),6.90(1H, d, J=7.6 Hz), 6.99(1H, t, J=7.6 Hz), 7.45(2H, d, J=8.6 Hz),7.49(1H, t, J=4.9 Hz), 8.44(2H, m), 9.00(1H, brs), 9.26(2H, d, J=4.9Hz); IR(KBr)cm⁻¹ : 2965, 1700, 1620, 1580, 1560, 1500, 1330, 1255, 1175,1085, 750

Example 55 (Synthesis of Compound No. 89)

The procedure described in Example 14 was repeated using Compound No. 3and 2-ethylaniline, to obtainN-(2-ethylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.07(3H, t, J=7.6 Hz), 1.29(9H, s), 2.50(2H,q, J=7.6 Hz), 2.84(2H, t, J=6.5 Hz), 3.90(3H, s), 4.94(2H, t, J=6.5 Hz),6.78(1H, t, J=7.6 Hz), 6.93(1H, d, J=7.6 Hz), 6.97˜7.32(6H), 7.43(1H, t,J=4.6 Hz), 7.43(2H, d, J=8.55 Hz), 8.43(2H, d, J=8.5 Hz), 8.59(1H, brs),8.65(2H, d, J=4.6 Hz), 8.83(1H,b IR(KBr)cm⁻¹ : 2965, 1670, 1618, 1499,1455, 1384, 1255, 1175, 1083, 752

Example 56 (Synthesis of Compound No. 90)

The procedure described in Example 54 was repeated using Compound No. 3and 1,2-phenylenediamine, to obtainN-(2-aminophenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.82(2H, t, J=6.5 Hz), 3.88(3H,s), 4.87(2H, t, J=6.5 Hz), 6.70˜7.14(8H), 7.33(1H, t,J=4.9 Hz), 7.42(2H,d, J=8.5 Hz), 8.36(2H, m), 8.77(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965,1665, 1620, 1580, 1560, 1500, 1342, 1255, 1175, 1080, 750

Example 57 (Synthesis of Compound No. 91)

The procedure described in Example 14 was repeated using Compound No. 3and phenylhydrazine, to obtainN'-phenyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionohydrazideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.30(9H, s), 2.77(2H, t, J=6.7 Hz), 3.94(3H,s), 4.80(2H, t, J=6.7 Hz), 6.24(1H, brs), 6.74˜7.24(9H), 7.33(1H, t,J=4.9 Hz), 7.46(2H, d, J=8.6 Hz), 8.47(2H, d, J=8.6 Hz), 8.90(2H, d,J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1680, 1620, 1580, 1560, 1500, 1340, 1255,1175, 1080, 775

Example 58 (Synthesis of Compound No. 92)

The procedure described in Example 54 was repeated using Compound No. 3and 2-aminopyridine, to obtainN-(2-pyridyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.77(2H, t, J=6.2 Hz), 3.86(3H,s), 4.86(2H, t, J=6.2 Hz), 6.68(1H, dt, J=7.8, 1.2 Hz), 6.86(1H, d,J=7.6 Hz), 6.90˜7.07(3H), 7.42(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.5 Hz),7.68(1H, dt, J=7.9, 1.8 Hz), 8.14(1H, d, J=8.3 Hz), 8.25(1H, m),8.39(2H, m), 8.49(1H, brs), 9.04(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965,1695, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 59 (Synthesis of Compound No. 93)

The procedure described in Example 14 was repeated using Compound No. 3and 2-isopropenylaniline, to obtainN-(2-isopropenylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.28(9H, s), 1.91(3H, s), 2.75(2H, t, J=6.0Hz), 3.88(3H, s), 4.85(1H, brs), 4.89(2H, t, J=6.0 Hz), 5.16(1H, brs),6.63(1H, t, J=7.4 Hz), 6.88(1H, d, J=7.6 Hz), 6.92˜7.14(4H, m), 7.23(1H,m), 7.41(1H, t, J=4.6 Hz), 7.41(2H, d, J=8.6 Hz), 7.96(1H, brs),8.09(1H, d, J=8.0 Hz), 8.39(2H, m), 8.92(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ :2965, 1685, 1620, 1580, 1560, 1500, 1345, 1255, 1175, 1085, 750

Example 60 (Synthesis of Compound No. 94)

The procedure described in Example 14 was repeated using Compound No. 3and 2-(methylthio)aniline, to obtainN-(2-methylthiophenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.24(3H, s), 2.82(2H, t, J=6.0Hz), 3.87(3H, s), 4.92(21H, t, J=6.0 Hz), 6.63(1H, t, J=7.4 Hz),6.85(1H, d, J=7.1 Hz), 6.89˜7.02(2H), 7.10(1H, dt, J=7.6, 1.2 Hz),7.26(1H, m), 7.41(1H, t, J=4.6 Hz), 7.41(2H, d, J=8.6 Hz), 8.12(1H, d,J=8.1 Hz), 8.36(2H, m), 8.55(1H, brs), 8.93(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹: 2960, 1685, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1080, 775

Example 61 (Synthesis of Compound No. 95)

The procedure described in Example 14 was repeated using Compound No. 3and 2-t-butylaniline, to obtainN-(2-t-butylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(18H, s), 2.86(2H, t, J=6.4 Hz), 3.91(3H,s), 4.96(2H, t, J=6.6 Hz), 6.74˜7.54(9H), 8.42(2H, m), S. 56(2H, m),8.73(1H, brs), 8.83, H, brs), 8.99(2H, d, J=4.9 Hz), IR(KBr)cm⁻¹ : 2965,1675, 1620, 1580, 1560, 1500, 1345, 1255, 1175, 1080, 775

Example 62 (Synthesis of Compound No. 96)

The procedure described in Example 54 was repeated using Compound No. 3and 3-aminopyridine, to obtainN-(3-pyridyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s) 2.81(2H, to J=6.2 Hz), 3.82(3H,s), 4.85(2H, t, J=6.2 Hz), 6.73(1H, dt, J=7.7, 1.2 Hz), 6.85(1H, dd,J=8.1, 1.2 Hz), 6.90(1H, d, J=8.1 Hz), 6.98(1H, dt, J=7.7, 1.5 Hz),7.22(1H, dd, J=8.3, 4.6 Hz), 7.41(1H, t, J=4.9 Hz), 7.43(2H, d, J=9.0Hz), 8.08(1H, brd, J=8.3 Hz), 8.33(1H, dd, J=4.6, 1.2 Hz), 8.34(2H, m),8.46(1H, d, J=2.7 Hz), 8.61(1H, brs) 8.93(1H, d, J=4.9 Hz) IR(KBr)cm⁻¹ :2965, 1695, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 63 (Synthesis of Compound No. 97)

The procedure described in Example 54 was repeated using Compound No. 2and 2-aminopyridine, to obtain N-(2-pyridyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow powder.

¹ NMR(CDCl₃, ppm, TMS): 1.28(9H5 s), 3.93(3H, s), 5.12(2H, s),6.80˜7.16(5H), 7.30˜7.50(3H), 7.65(1H, t, J=7.2 Hz), 8.12(1H, d, J=8.3Hz), 8.27(1H, m), 8.37(2H, m), 8.58(1H, brs), 8.99(2H, m) IR(KBr)cm⁻¹ :2965, 1705, 1620, 1583, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 64 (Synthesis of Compound No. 98)

The procedure described in Example 54 was repeated using Compound No. 4and 2-aminopyridine, to obtainN-(2-pyridyl)-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.05(2H, m), 2.23(2H, t, J=7.1Hz), 3.88(3H, s), 4.54(2H, t, J=5.7 Hz), 6.80˜7.20(5H), 7.41(1H, t,J=4.9 Hz), 7.42(2H, d, J=8.8 Hz), 7.75(1H, dt, J=7.9, 1.7 Hz), 8.21(1H,m), 8.22(1H, d, J=7.8 Hz), 8.35(2H, m), 9.01(2H, d, J=4.9 Hz)IR(KBr)cm⁻¹ : 2960, 1695, 1615, 1580, 1560, 1500, 1340, 1255, 1175,1080, 750

Example 65 (Synthesis of Compound No. 99)

The procedure described in Example 54 was repeated using Compound No. 3and 2,6-diisopropylaniline, to obtainN-(2,6-diisopropylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.05(12H, m), 1.29(9H, s), 2.93(2H, t, J=6.8Hz), 3.10(2H, sep, J=6.8 Hz), 3.99(3H, s), 4.99(2H, t, J=6.8 Hz),6.89(1H, t, J=7.6 Hz), 7.01(1H, d, J=7.8 Hz), 7.20(1H, d, J=7.8 Hz),7.07˜7.23(5H), 7.34(1H, t, J=7.8 Hz), 7.45(2H, d, J=8.3 Hz), 8.23(2H, d,J=4.4 Hz), 8.48(2H, m), 8.94(1H, brs), 9.70(1H, brs); IR(KBr)cm⁻¹ :2965, 1665, 1620, 1580, 1560, 1500, 1345, 1255, 1175, 1085, 750

Example 66(synthesis of Compound No. 100)

The procedure described in Example 14 was repeated using Compound No. 3and allylamine, to obtainN-allyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinylp)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.63(2H, t, J=6.2 Hz), 3.81(2H,t, J=35.5 Hz), 3.93(3H, s), 4.79(2H, t, J=6.2 Hz), 5.03(1H, m), 5.09(1H,m), 5.75(1H, m), 6.84(1H, t, J=7.8 Hz), 6.97(2H, m), 7.10(1H, t, J=7.7Hz), 7.42(1H, t, J=4.6 Hz), 7.42(2H, d, J=8.3 Hz), 8.38(2H, m), 8.80(1H,brs), 9.00(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ : 2965, 1655, 1580, 1560, 1500,1340, 1255, 1175, 1080, 750

Example 67 (Synthesis of Compound No. 101)

The procedure described in Example 54 was repeated using Compound No. 2and 2-amino-3-methylpyridine, to obtainN-(3-methyl-2-pyridyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.30(9H, s), 2.11(3H, s), 3.86(3H, s),5.20(2H, s), 6.81(1H, t, J=7.6 Hz), 6.88˜7.03(2H, m), 7.10(1H, m),7.11(1H, dd, J=7.6, 4.6 Hz), 7.43(1H, t, J=4.9 Hz) 7.44(2H, d, J=8.6Hz), 7.53(1H, m) 8.26(1H, m) 8.38(2H, m) 9.00(2H, d, J=4.9 Hz)

Example 68 (Synthesis of Compound No. 102)

The procedure described in Example 14 was repeated using Compound No. 3and 1-naphthylamine, to obtainN-(1-naphthyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 29(9H, s), 2.96(2H, t, J=6.2 Hz), 3.83(3H, s),5.01(2H, t, J=6.2 Hz), 6.75(1H, t, J=7.3 Hz), 6.83(1H, d, J=7.8 Hz),6.99(2H, m), 7.14(1H, m), 7.30(1H, t, J=7.6 Hz), 7.37˜7.51(4H, m),7.67(1H, d, J=7.1 Hz), 7.74(1H, d, J=8.3 Hz), 7.83(2H, m), 8.40(2H, m),8.50(2H, m), 9.15(1H, brs); IR(KBr)cm⁻¹ : 2965, 1670, 1580, 1560, 1500,1340, 1255, 1175, 1080, 750

Example 69 (Synthesis of Compound No. 103)

The procedure described in Example 14 was repeated using Compound No. 3and 2-aminothiazoline, to obtainN-(2-thiazolinyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s) 2.95(2H, t, J=6.4 Hz), 3.41(2H, t,J=8.6 Hz), 3.92(3H, s), 4.02(2H, t, J=8.6 Hz), 4.83(2H, t, J=6.4 Hz),6.84(1H, dt, J=7.7, 1.5 Hz), 6.96(1H, dd, J=7.7, 1.5 Hz), 6.99(1H, dd,J=7.7, 1.7 Hz), 7.07(1H, dt, J=7.7, 1.7 Hz), 7.42(2H, d, J=9.0 Hz),7.44(1H, t, J=4.9 Hz), 8.34(2H, m), 9.05(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ :2965, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 70 (Synthesis of Compound No. 104)

The procedure described in Example 54 was repeated using Compound No. 3and aminopyrazine, to obtainN-(2-pyrazinyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.85(2H, t, J=6.4 Hz), 3.88(3H,s), 4.86(2H, t, J=6.4 Hz), 6.71(1H, t, J=8.1 Hz), 6.87(1H, d, J=7.3 Hz),6.96(2H, m), 7.43(3H, m), 8.22(1H, dd, J=2.4, 1.5 Hz), 8.34(1H, d, J=2.4Hz), 8.40(3H, m), 8.59(1H, brs), 9.05(2H, d, J=4.9 Hz), 9.46(1H, s)IR(KBr)cm⁻¹ : 2960, 1700, 1580, 1560, 1500, 1345.1255, 1085, 750

Example 71 (Synthesis of Compound No. 105)

The procedure described in Example 54 was repeated using Compound No. 3and 2-aminopyrimidine, to obtainN-(2-pyrimidinyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.13(2H, t, J=6.4 Hz), 3.90(3H,s), 4.90(2H, t, J=6.4 Hz), 6.77(1H, t, J=8.1 Hz), 6.91(1H, d, J=7.1 Hz),6.99(1H, t, J=4.9 Hz), 7.03(2H, m), 7.42(3H, m)

Example 72 (Synthesis of Compound No. 106)

The procedure described in Example 14 was repeated using Compound No. 2and 2-pyridylhydrazine, to obtainN'-(2-pyridyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetohydrazideas a pale yellow powder.

Example 73 (Synthesis of Compound No. 107)

The procedure described in Example 14 was repeated using Compound No. 3and 2-pyridylhydrazine, to obtainN'-(2-pyridyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionohydrazideas a pale yellow powder.

Example 74 (Synthesis of Compound No. 68)

The procedure described in Example 14 was repeated using Compound No. 3and 2,6-dimethylaniline, to obtainN-(2,6-dimethylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.14(6H, s), 2.86(2H, t, J=6.7Hz), 3.88(3H, s), 4.96(2H, t, J=6.7 Hz), 6.83(1H, t, J=7.8 Hz), 6.91(1H,d, J=8.1 Hz), 6.95˜7.16(6H, m), 7.44(2H, d, J=8.8 Hz), 8.40(2H, m),8.49(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ : 2965, 1670, 1620, 1580, 1560, 1500,1345, 1255, 1175, 1080, 750

Example 75 (Synthesis of Compound No. 66)

The procedure described in Example 6 was repeated using Compound No. 2and methanol, to obtainmethyl[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.71(3H, s), 4.00(3H, s),5.14(2H, s), 6.89(1H, t, J=8.1 Hz), 7.00(1H, d, J=8.1 Hz), 7.12(1H, t,J=8.1 Hz), 7.32(1H, m), 7.41(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.3 Hz),8.37(2H, m), 8.99(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2960, 1760, 1620, 1580,1560, 1500, 1345, 1255, 1175, 1085, 750

Example 76 (Synthesis of Compound No. 67)

The procedure described in Example 6 was repeated using Compound No. 4and methanol, to obtain methyl4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyrateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.95(2H, m), 2.19(2H, t, J=7.3Hz), 3.63(3H, s), 3.90(3H, s), 4.50(2H, t, J=6.1 Hz), 6.84(1H, dt,J=7.4, 1.6Hz), 6.92-7.01(2H, m), 7.09(1H, dt, J=8.1, 2.7 Hz), 7.42(1H,t, J=4.9 Hz), 7.42(2H, d, J=8.5 Hz), 8.34(2H, m), 9.05(2H, d, J=4.9 Hz)IR(KBr)cm⁻¹ : 2965, 1735, 1620, 1580, 1560, 1500, 1345, 1255, 1175,1085, 750

Example 77 (Synthesis of Compound No. 69)

The procedure described in Example 6 was repeated using Compound No. 3and isopropyl alcohol, to obtain isopropyl3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.16(6H, d, J=6.3 Hz), 1.29(9H, s), 2.65(2H,t, J=6.2 Hz), 3.93(3H, s), 4.77(2H, t, J=6.3 Hz), 4.95(1H, sep, J=6.3Hz), 6.83(1H, t, J=7.8 Hz), 6.96(1H, dd, J=8.3, 1.5 Hz), 7.00˜7.15(2H,m), 7.41(2H, d, J=8.5 Hz), 7.42(1H, t, J=4.9 Hz), 8.30˜8.40(2H, m),9.01(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 2965, 1730, 1620, 1580, 1560, 1500,1345, 1255, 1175, 1085, 750

Example 78 (Synthesis of Compound No. 54)

The procedure described in Example 14 was repeated using Compound No. 2and N-benzylethanolamine, to obtainN-benzyl-N-(2-hydroxyethyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow oil.

¹ H-NMR(CDCl₃,ppm, TMS): 1.29(9H, s), 3.47(2H, m), 3.74(2H, m), 4.03(3H,s), 4.57(2H, s), 5.56(2H, s), 6.87-7.20(8H, m), 7.41(1H, t, J=4.9 Hz),7.42(2H, d, J=8.3 Hz), 7.53(1H, m), 8.42(2H, m) 8.88(2H, d, J=4.9 Hz);IR(KBr)cm⁻¹ : 3430, 2965, 1665, 1620, 1580, 1560, 1500, 1345, 1255,1175, 1085, 750

Example 79 (Synthesis of Compound No. 55)

The procedure described in Example 14 was repeated using Compound No. 3and 2-(aminomethyl)pyridine, to obtainN-(2-pyridylmethyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.71(2H, t, J=6.4 Hz), 3.91(3H,s), 4.63(2H, d, J=5.4 Hz), 4.83(2H, t, J=6.4 Hz), 6.81(1H, dt, J=7.8,1.5 Hz), 6.93(1H, dd, J=7.8, 1.5 Hz), 6.98(1H, brd, J=7.8 Hz), 7.06(1H,dd, J=7.8, 1.5 Hz), 7.42(2H, d, J=8.3 Hz), 7.43(1H, t, J=4.9 Hz),7.51(1H, d, J=7.8 Hz), 7.80-7.95(2H, m), 8.32(2H, m), 8.49(1H, d, J=4.9Hz), 9.00(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 2965, 1665, 1620, 1580, 1560,1500, 1345, 1255, 1175, 1085, 750

Example 80 (Synthesis of Compound No. 56)

The procedure described in Example 14 was repeated using Compound No. 3and 2-(2-aminoethyl)pyridine, to obtainN-[2-(2-pyridyl)ethyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.62(2H, t, J=6.2 Hz), 3.20(2H,t, J=6.2 Hz), 3.68(2H, m), 3.95(3H, s), 4.73(2H, d, J=6.2 Hz), 6.83(1H,brt, J=7.7 Hz), 6.93-7.03(2H, m), 7.09(1H, dt, J=7.7, 1.5 Hz),7.31-7.49(3H, m), 7.42(2H, d, J=8.6 Hz), 7.45(1H, t, J=4.9 Hz), 7.84(1H,t, J=7.4 Hz), 8.32(2H, m), 8.48(1H, d, J=4.6 Hz), 9.04(2H, d, J=4.9 Hz)IR(KBr)cm⁻¹ : 2965, 1655, 1620, 1580, 1560, 1500, 1340, 1255, 1175,1080, 750

Example 81 (Synthesis of Compound No. 57)

The procedure described in Example 14 was repeated using Compound No. 3and a-methylbenzylamine, to obtainN-(α-methylbenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.62(2H, t, J=6.2 Hz), 3.20(2H,t, J=6.2 Hz), 3.68(2H, m), 3.95(3H, s), 4.73(2H, d, J=6.2 Hz), 6.83(1H,brt, J=7.7 Hz), 6.93-7.03(2H, m), 7.09(1H, dt, J=7.7, 1.5 Hz),7.31-7.49(3H, m), 7.42(2H, d, J=8.6 Hz), 7.45(1H, t, J=4.9 Hz), 7.84(1H,t, J=7.4 Hz), 8.32(2H, m), 8.48(1H, d, J=4.6 Hz), 9.04(2H, d, J=4.9 Hz)IR(KBr)cm⁻¹ : 2965, 1655, 1620, 1580, 1560, 1500, 1340, 1255, 1175,1080, 750

Example 82 (Synthesis of Compound No. 58)

The procedure described in Example 14 was repeated using Compound No. 3and N-benzylmethylamine, to obtainN-benzyl-N-methyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.28(9H, s), 2.77(2H, t, J=6.6 Hz), 2.85(3H,s), 3.96(3H, s), 4.53(2H, s), 4.91(2H, t, J=6.6 Hz), 6.80(1H, t, J=7.4Hz), 6.96(1H, d, J=8.1 Hz), 7.01-7.31(7H, m), 7.40(2H, d, J=8.5 Hz),7.41(1H, t, J=4.9 Hz), 8.32(2H, m), 9.00(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ :2965, 1645, 1620, 1580, 1560, 1500, 1345, 1255, 1175, 1085, 750

Example 83 (Synthesis of Compound No. 59)

The procedure described in Example 14 was repeated using Compound No. 3and N-methylaniline, to obtainN-methyl-N-phenyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.28(9H, s), 2.45(2H, t, J=6.1 Hz), 3.18(3H,s), 3.96(3H, s), 4.80(2H, t, J=6.1 Hz), 6.81(1H, t, J=7.3 Hz),6.90-7.12(5H, m), 7.19-7.31(3H, m), 7.40(2H, d, J=8.5 Hz), 7.42(1H, t,J=4.9 Hz), 8.32(2H, m), 9.00(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1655,1620, 1580, 1560, 1500, 1345, 1255, 1175, 1080, 750

Example 84 (Synthesis of Compound No. 60)

The procedure described in Example 14 was repeated using Compound No. 3and 2-(trifluoromethyl)benzylamine, to obtainN-(2-trifluoromethylbenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.28(9H, s), 2.67(2H, t, J=6.2 Hz), 3.87(3H,s), 4.55(2H, d, J=5.9 Hz), 4.82(2H, t, J=6.2 Hz), 6.79(1H, t, J=7.6 Hz),6.88-7.00(2H, m), 7.06(1H, t, J=8.1 Hz), 7.22-7.47(6H, m), 7.58(1H, d,J=7.6 Hz), 8.34(2H, m), 8.87(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1665,1620, 1580, 1560, 1500, 1315, 1255, 1165, 1080, 750

Example 85 (Synthesis of Compound No. 61)

The procedure described in Example 14 was repeated using Compound No. 3and furfurylamine, to obtainN-furfuryl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.62(2H, t, J=6.3 Hz), 3.92(3H,s), 4.35(2H, d, J=5.4 Hz), 4.78(2H, t, J=6.3 Hz), 6.12(1H, t, J=3.2 Hz),6.22(1H, dd, J=3.2, 1.9 Hz), 6.82(1H, t, J=7.8 Hz), 6.84˜7.02(3H, m),7.09(1H, t, J=7.8 Hz), 7.22(1H, d, J=1.9 Hz), 7.40(1H, d, J=4.9 Hz),7.43(2H, d, J=8.3 Hz), 8.41(2H, m), 8.82(1H, brs), 8.96(2H, d, J=4.9 Hz)IR(KBr)cm⁻¹ : 2965, 1660, 1620, 1580, 1560, 1500, 1340, 1255, 1175,1080, 750

Example 86 (Synthesis of Compound No. 62)

The procedure described in Example 14 was repeated using Compound No. 2and 2-methoxybenzylamine, to obtainN-(2-methoxybenzyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 3.69(3H, s), 3.78(3H, s),4.34(2H, d, J=6.1 Hz), 5.01(2H, s), 6.46(1H, m), 6.71(1H, dt, J=7.81.5Hz), 6.78(1H, d, J=8.3 Hz), 6.80-6.89(2H, m), 6.98(1H, d, J=7.8 Hz),6.99(1H, t, J=7.8 Hz), 7.08(1H, dd, J=7.8, 1.5 Hz), 7.21(1H, dt, J=7.8,1.5 Hz), 7.42(1H, m), 7.43(2H, d, J=8.3 Hz), 8.38(2H, m), 8.96(2H, d,J=4.9 Hz); IR(KBr)cm⁻¹ : 2965, 1685, 1620, 1580, 1560, 1500, 1340, 1245,1175, 1080, 775

Example 87 (Synthesis of Compound No. 63)

The procedure described in Example 14 was repeated using Compound No. 2and α-methylbenzylamine, to obtainN-(α-methylbenzyl)-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.30(3H, d, J=7.1 Hz), 3.80(3H,s), 4.94(1H, d, J=15.1 Hz), 4.99(1H, d, J=15.1 Hz), 5.12(1H, m),6.38(1H, d, J=8.1 Hz), 6.73(1H, dt, J=7.8, 1.5 Hz), 6.81-6.92(2H, m),7.03(1H, t, J=7.8 Hz), 7.09-7.30(5H, m), 7.42(1H, m), 7.43(2H, d, J=8.3Hz), 8.38(2H, m), 8.98(2H, d, J=4.9 Hz)

Example 88 (Synthesis of Compound No. 64)

The procedure described in Example 14 was repeated using Compound No. 3and 2-aminothiazole, to obtainN-(2-thiazolyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a yellowish white powder.

¹ H-NMR(DMSO-d₆, ppm, TMS): 1.27(9H, s), 2.72(2H, m), 3.70(3H, s),4.61(2H, m), 6.54(1H, t, J=7.8 Hz), 6.61(1H, dd, J=7.8, 1.5 Hz),6.79(1H, dt, J=7.8, 1.5 Hz), 6.91(1H, dd, J=7.8, 1.5 Hz), 7.19(1H, d,J=3.7 Hz), 7.46(1H, d, J=3.7 Hz), 7.55(2H, d, J=8.3 Hz), 7.67(1H, t,J=4.6 Hz), 8.31(2H, d, J=8.3 Hz), 9.10(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ :2965, 1690, 1620, 1560, 1500, 1340, 1255, 1175, 1080, 750

Example 89 (Synthesis of Compound No. 65)

The procedure described in Example 14 was repeated using Compound No. 3and 2,5-dimethoxyaniline, to obtainN-(2,5-dimethoxyphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a brown oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.76(2H, t, J=6.0 Hz), 3.70(3H,s), 3.76(3H, s), 3.86(3H, s), 4.89(2H, t, J=6.0 Hz), 6.56(1H, dd,J=9.0,2.9H 6.63(1H, dd, J=7.6, 1.5 Hz), 6.73(1H, d, J=8.8 Hz), 6.85(1H,dd, J=8.2, 1.3 Hz), 6.90-7.40(2H, m), 7.41(2H, d, J=8.8 Hz), 7.42(1H, t,J=4.9 Hz), 7.89(1H, s), 8.04(1H, d, J=2.9 Hz), 8.34(2H, m), 9.00(2H, d,J=4.9 Hz); IR(KBr)cm⁻¹ : 2965, 1685, 1620, 1580, 1560, 1500, 1340, 1255,1175, 1085, 750

Example 90 (Synthesis of Compound No. 70)

The procedure described in Example 14 was repeated using Compound No. 3and 2-aminophenol, to obtainN-(2-hydroxyphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.85(2H, m), 3.85(3H, s),4.82(2H, m), 6.67-7.13(8H, m), 7.37(1H, m), 7.43(2H, d, J=8.3 Hz),8.37(2H, brs), 8.85(2H, m), 8.95(1H, brs) IR(KBr)cm⁻¹ : 2965, 1655,1615, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 91 (Synthesis of Compound No. 71)

The procedure described in Example 14 was repeated using Compound No. 3and 2-phenylglycinol, to obtainN-(α-hydroxymethylbenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR (CDCl₃, ppm, TMS): 1.28(9H, s), 2.67(2H, m), 3.77(2H, m),3.91(3H, s), 4.80(2H, m), 5.00(1H, m), 6.72-7.24(11H, m), 7.40(1H, m),7.41(2H, d, J=8.8 Hz), 8.32(2H, m), 8.92(2H, m); IR(KBr)cm⁻¹ : 2965,1655, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 92 (Synthesis of Compound No. 72)

The procedure described in Example 14 was repeated using Compound No. 3and aminodiphenylmethane, to obtainN-diphenylmethyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.74(2H, t, J=6.4 Hz), 3.93(3H,s), 4.82(2H, t, J=6.5 Hz), 6.26(1H, d, J=8.0 Hz), 6.70-7.25(14H, m),7.29(1H, t, J=4.6 Hz), 7.43(2H, d, J=8.6 Hz), 8.40(2H, d, J=8.6 Hz),8.75(2H, d, J=4.6 Hz), 8.84(1H, brs) IR(KBr)cm⁻¹ : 2965, 1655, 1620,1580, 1560, 1500, 1340, 1255, 1175, 1080, 750

Example 93 (Synthesis of Compound No. 73)

The procedure described in Example 14 was repeated using Compound No. 3and 4-nitrobenzylamine, to obtainN-(4-nitrobenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.28(9H, s), 2.72(2H, t, J=6.1 Hz), 3.93(3H,s), 4.46(2H, d, J=6.1 Hz), 4.84(2H, t, J=6.1 Hz), 6.72˜7.24(5H, m),7.32(2H, d,J=8.8 Hz), 7.40(1H, m), 7.42(2H, d, J=8.3 Hz), 8.03(2H, d,J=8.8 Hz), 8.36(2H, m), 8.091(2H (1H, d, J=4.6 Hz) IR(KBr)cm⁻¹ : 2965,1665, 1620, 1580, 1560, 1500, 1345, 1255, 1175, 1080, 750

Example 94 (Synthesis of Compound No. 74)

The procedure described in Example 14 was repeated using Compound No. 3and 2-phenylglycinonitrile, to obtainN-(phenylcyanomethyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s) 2.681(2H, s)t, J=6.6 Hz), 3.95(3Hz s), 4.74(2H, dt, J=1.15, 6.6 Hz), 4.87(1H, dt, J=11.5, 6.6 Hz),6.28(1H, d, J=8.8 Hz), 6.77-7.50(12H, m), 8.02(1H, m), 8.42(2H, m),8.83(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1685, 1620, 1580, 1560, 1500,1340, 1255, 1175, 1080, 750

Example 95 (Synthesis of Compound No. 75)

The procedure described in Example 14 was repeated using Compound No. 3and 2-methylallylamine, to obtainN-(2-methylallyl)-3-[6-(4-t-butylphenylsulfonylamino-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide asa pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.67(3H, s), 2.65(2H, t, J=6.3Hz), 3.74(2H, d, J=5.9 Hz), 3.94(3H, s), 4.75(2H, brs), 4.80(2H, t,J=6.3 Hz), 6.50(1H, brs), 6.84(1H, t, J=8.0 Hz), 6.94-7.03(2H, m),7.11(1H, t, J=8.1 Hz), 7.43(2H, d, J=8.5 Hz), 7.43(1H, t, J=4.6 Hz),8.38(2H, m), 8.99(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ : 2965, 1650, 1620, 1580,1560, 1500, 1340, 1255, 1175, 1085, 750

Example 96 (Synthesis of Compound No. 76)

The procedure described in Example 14 was repeated using Compound No. 3and cyclopropylamine, to obtainN-cyclopropyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 0.40(2H, m), 0.70(2H, m), 1.29(9H, s),2.54(21H, t, J=6.8 Hz), 2.58(1H, m), 3.94(3H, s), 4.75(2H, t, J=5.4 Hz),6.33(1H, brs), 6.84(1H, t, J=7.2 Hz), 6.92-7.02(2H, m), 7.10(1H, t,J=8.1 Hz), 7.38-7.48(3H, m), 8.42(2H, m), 9.02(2H, m) IR(KBr)cm⁻¹ :2965.1655, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 97 (Synthesis of Compound No. 77)

The procedure described in Example 14 was repeated using Compound No. 3and methylamine, to obtainN-methyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.58(2H, t, J=6.4 Hz), 2.70(3H,d, J=4.4 Hz), 3.93(3H, s), 4.76(2H, t, J=6.4 Hz), 6.85(1H, t, J=7.3 Hz),6.92-7.02(2H, m), 7.10(1H, t, J=7.8 Hz), 7.37-7.48(31H, m), 8.37(2H, m),9.01(2H, m); IR(KBr)cm⁻¹ : 2965, 1655, 1620, 1580, 1560, 1500, 1340,1255, 1170, 1080, 750

Example 98 (Synthesis of Compound No. 78)

The procedure described in Example 14 was repeated using Compound No. 3and dimethylamine, to obtainN,N-dimethyl-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.70(2H, t, J=6.8 Hz), 2.88(3H,s), 2.93(3H, s), 3.95(3H, s), 4.85(2H, t, J=6.8 Hz), 6.82(1H, t, J=6.4Hz), 6.93-7.13(3H, m), 7.36-7.45(3H, m), 8.33(2H, m), 9.00(2H, m)IR(KBr)cm⁻¹ : 2965, 1645, 1620, 1580, 1560, 1500, 1340, 1255, 1175,1085, 750

Example 99 (Synthesis of Compound No. 79)

The procedure described in Example 14 was repeated using Compound No. 3and 2-chloroaniline, to obtainN-(2-chlorophenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.80(2H, t, J=6.1 Hz), 3.86(3H,s), 4.90(2H, t, J=6.0 Hz), 6.60(1H, t, J=7.3 Hz), 6.85(1H, d, J=7.6 Hz),6.89-7.02(2H, m), 7.06(1H, dt, J=7.7, 1.6 Hz), 7.26(1H, dt, J=7.8, 1.5Hz), 7.33(1H, dd, J=8.1, 1.5 Hz), 7.40(1H, t, J=4.9 Hz), 7.42(2H, d,J=8.3 Hz), 7.99(1H, brs), 8.18(1H, d, J=8.1 Hz), 8.38(2H, m), 8.93(2H,d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1695, 1620, 1580, 1560, 1500, 1340,1255, 1175, 1085, 775

Example 100 (Synthesis of Compound No. 80)

The procedure described in Example 14 was repeated using Compound No. 3and 2,6-difluorobenzylamine, to obtainN-(2,6-difluorobenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.59(2H, t, J=6.2 Hz), 3.94(3H,s), 4.46(2H, d, J=5.6 Hz), 4.77(2H, t, J=6.2 Hz), 6.43(1H, m),6.71-7.22(7H, m), 7.40(1H, m), 7.43(2H, d, J=8.3 Hz), 8.40(2H, d, J=8.3Hz), 8.73(1H, brs), 8.97(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 2965, 1665,1625, 1580, 1560, 1500, 1340, 1245, 1175, 1080, 750

Example 101 (Synthesis of Compound No. 81)

The procedure described in Example 14 was repeated using Compound No. 3and 1-aminoindan, to obtainN-(1-indanyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.67(1H, m), 2.52(2H, m),2.68(2H, t, J=6.5 Hz), 2.85(2H, m), 3.92(3H, s), 4.84(2H, t, J=6.4 Hz),5.48(1H, m), 6.47(1H, d, J=8.5 Hz), 6.80(1H, dt, J=7.7, 1.5 Hz),6.90-7.25(7H, m), 7.28(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.8 Hz), 8.39(2H,d, J=8.6 Hz), 8.70(2H, d, J=4.6 Hz) IR(KBr)cm⁻¹ : 2965, 1655, 1620,1580, 1560, 1500, 1345, 1255, 1175, 1080, 750

Example 102 (Synthesis of Compound No. 82)

The procedure described in Example 14 was repeated using Compound No. 3and 2-thiophenemethylamine, to obtainN-(2-thenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.65(2H, t, J=6.4 Hz), 3.93(3H,s), 4.55(2H, d, J=5.9 Hz), 4.79(2H, t, J=6.4 Hz), 6.79-7.16(7H, m),7.38(1H, t, J=4.9 Hz), 7.44(2H, d, J=8.6 Hz), 8.41(2H, d, J=8.5 Hz),8.72(1H, brs), 8.91(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965, 1655, 1620,1580, 1560, 1500, 1340, 1255, 1175, 1080, 750

Example 103 (Synthesis of Compound No. 83)

The procedure described in Example 14 was repeated using Compound No. 3and 2,4-dimethoxybenzylamine, to obtainN-(2,4-dimethoxybenzyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.59(2H, t, J=6.2 Hz), 3.71(3H,s), 3.77(3H, s), 3.93(3H, s), 4.31(2H, d, J=5.6 Hz), 4.79(2H, t, J=6.2Hz), 6.31-6.51(3H, m), 6.81(1H, t, J=7.7 Hz), 6.95(1H, d, J=7.6 Hz),6.90-7.14(3H, m), 7.37(1H, t, J=4.9 Hz), 7.42(2H, d, J=8.5 Hz), 8.39(2H,d, J=8.3 Hz), 8.82(1H, brs), 8.93(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ : 2965,1655, 1620, 1580, 1560, 1500, 1340, 1255, 1175, 1080, 775

Example 104 (Synthesis of Compound No. 84)

The procedure described in Example 54 was repeated using Compound No. 3and 5-amino-1-ethylpyrazole, to obtainN-(1-ethyl-5-pyrazolyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.29(3H, t, J=7.2 Hz), 2.88(2H,t, J=6.6 Hz), 3.94(2H, q, J=7.2 Hz), 3.95(3H, s), 4.89(2H, t, J=6.6 Hz),6.15(1H, d, J=1.7 Hz), 6.85(1H, t, J=7.1 Hz), 6.94-7.07(2H, m), 7.12(1H,t, J=7.3 Hz), 7.32(1H, m), 7.45(2H, d, J=8.5 Hz), 7.52(1H, d, J=1.7 Hz),8.45(2H, m), 8.53(2H, m), 9.70(1H, brs); IR(KBr)cm⁻¹ : 2965, 1700, 1620,1580, 1560, 1500, 1340, 1255, 1175, 1085, 750

Example 105 (Synthesis of Compound No. 85)

The procedure described in Example 54 was repeated using Compound No. 3and 2-aminobenzofluoride, to obtainN-(2-trifluoromethylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.80(2H, t, J=6.2 Hz), 3.87(3H,s), 4.89(2H, t, J=6.2 Hz), 6.72(1H, t, J=7.6 Hz), 6.88(1H, d, J=7.6 Hz),6.92-7.04(2H, m), 7.31(11H, d, J=7.8 Hz), 7.36(1H, t, J=4.9 Hz),7.42(2H, d, J=8.6 Hz), 7.55(1H, t, J=7.7 Hz), 7.61(1H, d, J=7.8 Hz),7.90(1H, d, J=8.1 Hz), 8.17(1H, brs), 8.39(2H, m), 8.83(2H, d, J=4.6Hz); IR(KBr)cm⁻¹ : 2965, 1685, 1620, 1580, 1560, 1500, 1340, 1255, 1170,1080, 750

Example 106 (Synthesis of Compound No. 86)

The procedure described in Example 54 was repeated using Compound No. 3and 2-nitroaniline, to obtainN-(2-nitrophenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxyl]propionamideas a pale yellow oil.

¹ H-NMR(CDCl.sub. 3, ppm, TMS): 1.29(9H, s), 2.82(2H, t, J=5.9 Hz),3.84(1H, s) 4.90(2H, t, J=5.9 Hz), 6.59(1H, m), 6.74-6.96(7H, m),7.19(1H, dt, J=7.8, 1.5 Hz), 7.36-7.47(3 H, m), 7.63(1H, dt, J=7.9, 1.5Hz), 8.18(2H, dd, J=8.4, 1.6Hz), 8.37(2H, m), 8.60(1H, brs), 8.68(1H, d,J=8.6Hz), 9.00(2H, d, J=4.6 Hz); IR(KBr)cm⁻¹ : 2965, 1695, 1580, 1560,1500, 1340, 1255, 1170, 1085, 745

Example 107 (Synthesis of Compound No. 87)

The procedure described in Example 54 was repeated using Compound No. 3and ethyl 2-aminobenzoate, to obtainN-(2-ethoxycarbonylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide as a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.37(3H, t, J=7.1 Hz), 2.80(2H,t, J=6.0 Hz), 3.86(3H, s), 4.30(2H, q, J=7.2 Hz), 4.90(2H, t, J=56.9Hz), 6.58(1H, dt, J=7.6, 1.7 Hz), 6.76-6.92(2H, m), 7.00(1H, d, J=7.1Hz), 7.08(1H, dt, J=8.1, 1.5 Hz), 7.40(1H, t, J=74.6 Hz), 7.41(2H, d,J=8.3 Hz), 7.52(1H, dt, J=8.6, 1.5 Hz), 8.01(1H, dd, J=8.1, 1.5 Hz),8.37(2H, d, J=8.5 Hz), 8.65(1H, d, J=8.6 Hz), 8.73(1H, brs), 9.00(2H, d,J=4.6 Hz); IR(KBr)cm⁻¹ : 2965, 1685, 1580, 1560, 1500, 1345, 1260, 1175,1085, 760

Example 108 (Synthesis of Compound No. 110)

The procedure described in Example 3 was repeated using4-t-butyl-N-[6-(2,2-dimethyl-3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide,to obtain3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-2,2-dimethylpropionicacid as a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.14(6H, s), 1.27(9H, s), 3.74(3H, s),4.48(2H, s), 6.50(1H, dt, J=7.4, 2.5 Hz), 6.83(1H, d, J=7.6 Hz),7.44(2H, d, J=8.8 Hz), 7.51(1H, t, J=4.9 Hz), 8.37(2H, m), 9.19(2H, d,J=4.9 Hz); IR(KBr)cm⁻¹ : 3400, 2965, 1720, 1620, 1560, 1500, 1345, 1255,1175, 1080, 750

Example 109 (Synthesis of Compound No. 111)

The procedure described in Example 3 was repeated using4-t-butyl-N-[6-(2,2-diethyl-3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide,to obtain2-[[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]]methyl-2-ethylbutanoicacid as a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 0.68(6H, t, J=7.3 Hz), 1.00-1.52(4H, m),1.29(9H, s), 3.84(3H, s), 4.58(2H, s), 6.70(1H, dt, J=7.6, 1.5 Hz),6.83-7.00(3H, m), 7.44(2H, d, J=8.8Hz), 7.48(1H, t, J=4.9Hz), 8.37(2H,m), 9.11(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 3400, 2965, 1720, 1620, 1560,1500, 1340, 1255, 1175, 1080, 750

Example 110 (Synthesis of Compound No. 112)

The procedure described in Example 3 was repeated using4-t-butyl-N-[6-(3-hydroxy-2-methylpropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide,to obtain3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-2-methylpropionicacid as a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.11(3H, d, J=7.1 Hz), 1.27(9H, s), 2.81(1H,m), 3.84(3H, s), 4.61(1H, dd, J=10.8.6.1 Hz), 4.70(1H, dd, J=10.8, 5.9Hz), 6.68(1H, dt, J=7.7, 1.7 Hz), 6.86(1H, dd, J=8.0, 1.2 Hz), 6.94(1H,t, J=8.3, 1.2 Hz), 7.01(1H, d, J=7.6 Hz), 7.42(2H, d, J=8.5 Hz),7.50(1H, t, J=4.9 Hz), 8.37(2H, m), 9.16(2H, d, J=4.9 Hz) IR(KBr)cm⁻¹ :3400, 2965, 1720, 1620, 1560, 1500, 1340, 1255, 1175, 1080, 750

Example 111 (Synthesis of Compound No. 117)

The procedure described in Example 3 was repeated using4-t-butyl-N-[6-(3-hydroxypropyloxy)-2-(4,6-dimethyl-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide,to obtain3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-dimethyl-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionicacid as a white powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.30(9H, s), 2.66(6H, s), 2.69(2H, t, J=6.5Hz), 3.91(3H, s), 4.74(2H, t, J=6.5 Hz), 6.79(1H, dt, J=7.8, 1.2 Hz),6.93(1H, dd, J=8.1 1.2 Hz), 6.98(11H, m), 7.04(1H, t, J=7.7 Hz),7.12(1H, s), 7.45(2H, d, J=8.8 Hz), 8.37(2H, m) IR(KBr)cm⁻¹ : 3385,2965, 1730, 1620, 1580, 1500, 1340, 1255, 1170, 1080, 750

Example 112 (Synthesis of Compound No. 124)

The procedure described in Example 3 was repeated using4-isopropyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide,to obtain3-[6-(4-t-isopropylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionicacid as a pale yellow powder.

¹ H-NMR(CDCl₃ -CD₃ OD, ppm, TMS): 1.23(6H, d, J=7.1 Hz), 2.62(2H, t,J=6.2 Hz), 2.94(1H, sep, J=7.1 Hz), 3.91(3H, s), 4.74(2H, t, J=6.2 Hz),6.85(1H, t, J=7.7 Hz), 6.90-7.04(2H, m), 7.10(1H, dt, J=7.7, 1.5 Hz),7.29(2H, d, J=8.3 Hz), 7.53(1H, t, J=4.6 Hz), 8.33(2H, m), 9.02(2H, d,J=4.6 Hz) IR(KBr)cm⁻¹ : 3385, 2965, 1730, 1620.1500, 1340, 1255, 1170,1080, 750

Example 113 (Synthesis of Compound No. 113)

The procedure described in Example 54 was repeated using Compound No.112 and 2-aminopyridine, to obtainN-(2-pyridyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-2-methylpropionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.19(3H, d, J=6.8 Hz), 1.29(9H, s), 3.04(1H,m), 3.86(3H, s), 4.42(1H, dd, J=10.7, 6.2 Hz), 4.89(1H, dd, J=10.7, 6.7Hz), 6.67(1H, dt, J=7.2, 1.7 Hz), 6.81-7.16(4H, m), 7.42(2H, d, J=8.5Hz), 7.43(1H, t, J=4.6 Hz), 7.69(1H, dt, J=7.8, 2.0 Hz), 8.15-8.25(2H,m), 8.36(2H, m), 9.06(2H, d, J=4.6 Hz), 9.14(1H, brs); IR(KBr)cm⁻¹ :2965, 1695, 1580, 1560, 1500, 1340, 1255, 1170, 1085, 750

Example 114 (Synthesis of Compound No. 114)

The procedure described in Example 14 was repeated using Compound No.112 and 2-isopropylaniline, to obtainN-(2-isopropylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]-2-methylpropionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 0.99(3H, d, J=6.8 Hz), 1.01(3H, d, J=6.8 Hz),1.17(3H, d, J=6.8 Hz), 1.23(9H, s), 2.91-3.08(2H, m), 3.86(3H, s),4.26(1H, dd, J=11.0, 6.8 Hz), 5.06(1H, dd, J=11.0,3.8 Hz), 6.77(1H, t,J=7.6 Hz), 6.91(1H, d, J=7.3 Hz), 6.96-7.34(7H, m), 7.38(2H, d, J=8.6Hz), 8.39(2H, m), 8.49(2H, m), 9.01(1H, brs) IR(KBr)cm⁻¹ : 2965, 1670,1580, 1560, 1500, 1345, 1255, 1175, 1080, 755

Example 115 (Synthesis of Compound No. 108)

The procedure described in Example 6 was repeated using Compound No. 3and methanol, to obtain methyl3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.68(2H, t, J=6.2 Hz), 3.60(3H,s), 3.92(3H, s), 4.77(2H, t, J=6.2 Hz), 6.83(1H, dt, J=7.6, 1.5 Hz),6.96(1H, d, J=7.1 Hz), 7.02(1H, m), 7.10(1H, t, J=7.6 Hz), 7.42(2H, d,J=8.5 Hz), 7.42(1H, t, J=4.9 Hz), 8.36(2H, m), 9.01(2H, d, J=4.9 Hz);IR(KBr)cm⁻¹ : 2960, 1740, 1580, 1560, 1500, 1340, 1255, 1175, 1080, 750

Example 116 (Synthesis of Compound No. 115)

The procedure described in Example 14 was repeated using Compound No.124 and 2-isopropylaniline, to obtainN-(2-isopropylphenyl)-3-[6-(4-isopropylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale brown oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.07(6H, d, J=6.8 Hz), 1.22(6H, d, J=6.8 Hz),2.86(2H, t, J=6.3 Hz), 2.92(1H, sep, J=6.8 Hz), 3.03(1H, sep, J=6.8 Hz),3.92(3H, s), 4.93(2H, t, J=6.3 Hz), 6.80(1H, t, J=7.4 Hz), 6.95(1H, d,J=7.6 Hz), 7.00-7.40(7H, m), 8.42(2H, m), 8.59(2H, m), 8.84(2H, m);IR(KBr)cm⁻¹ : 2965, 1670, 1580, 1560, 1500, 1345, 1255, 1170, 1085, 760

Example 117 (Synthesis of Compound No. 116)

The procedure described in Example 54 was repeated using Compound No.124 and 2-aminopyridine, to obtainN-(2-pyridyl)-3-[6-(4-isopropylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.22(6H, d, J=6.8 Hz), 2.77(2H, t, J=6.3 Hz),2.92(1H, sep, J=6.8 Hz), 3.86(3H, s), 4.86(2H, t, J=6.3 Hz), 6.68(1H,dt, J=7.7, 1.5 Hz), 6.86(1H, dd, J=8.1, 1.2 Hz), 6.90-7.06(3H, m),7.26(2H, d, J=8.6 Hz), 7.42(1H, t, J=4.9 Hz), 7.67(1H, dt, J=7.9, 2.0Hz), 8.14(1H, d, J=8.3 Hz), 8.25(1H, m), 8.39(2H, m), 8.52(1H, brs),9.04(2H, d, J=4.9 Hz); IR(KBr)cm⁻¹ : 2960, 1695, 1580, 1560, 1500, 1340,1255, 1170, 1085, 750

Example 118 (Synthesis of Compound No. 120)

The procedure described in Example 54 was repeated using Compound No.117 and 2-aminopyridine, to obtainN-(2-pyridyl)-3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-dimethyl-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.30(9H, s), 2.66(6H, s), 2.74(2H, t, J=6.1Hz), 3.84(3H, s), 4.87(2H, t, J=6.1 Hz), 6.65(1H, t, J=7.3 Hz),6.80-6.98(3H, s), 7.04(1H, m), 7.16(1H, s), 7.44(2H, d, J=8.3 Hz),7.69(1H, t, J=7.0 Hz), 8.15(1H, d, J=8.3 Hz), 8.22(1H, d, J=3.9 Hz),8.38(2H, m), 8.48(1H, brs); IR(KBr)cm⁻¹ : 2965, 1695, 1620, 1580, 1500,1345, 1255, 1170, 1085, 750

Example 119 (Synthesis of Compound No. 121)

The procedure described in Example 14 was repeated using Compound No.117 and 2-isopropylaniline, to obtainN-(2-isopropylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-dimethyl-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.04(6H, d, J=6.8 Hz), 1.30(9H, s), 2.54(6H,s), 2.82(2H, t, J=6.2 Hz), 2.88(1H, sep, J=6.8 Hz), 3.86(3H, s),4.91(2H, t, J=6.2 Hz), 6.67-7.54(11H, m), 7.75(1H, brs), 8.40(2H, m);IR(KBr)cm⁻¹ : 2965, 1670, 1620, 1575, 1500, 1345, 1255, 1180, 1085, 755

Example 120 (Synthesis of Compound No. 122)

The procedure described in Example 14 was repeated using Compound No.118 and 2-isopropylaniline, to obtainN-(2-isopropylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-diethoxy-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionamideas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.07(6H, m), 1.29(9H, s), 1.43(6H, m),2.71-2.92(3H, m), 3.86(3H, brs), 4.54(4H, m), 4.88(2H, t, J=6.0 Hz),6.12(1H, s), 6.54-7.52(10H, m), 8.35(2H, m); IR(KBr)cm⁻¹ : 2965, 1670,1590, 1500, 1345, 1255, 1180, 1085, 775

Example 121 (Synthesis of Compound No. 123)

The procedure described in Example 14 was repeated using Compound No.119 and 2-isopropylaniline, to obtainN-(2-isopropylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-diisopropyl-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionamideas a pale yellow powder.

¹ H-NMR(CDCl₃, ppm, TMS): 1.07(6H, m), 1.30(9H, s), 1.41(12H, d, J=6.1Hz), 2.75-2.95(3H, m), 3.86(3H, brs), 4.88(2H, t, J=6.0 Hz), 5.52(2H,sep, J=6.1 Hz), 6.05(1H, s), 6.54-7.46(10H, m), 8.32(2H, m); IR(KBr)cm⁻¹: 2965, 1670, 1620, 1575.1500, 1345, 1255, 1175, 1105, 775

Example 122 (Synthesis of Compound No. 109)

(1) To 3-benzyloxy-1-propanol (1.66 g) dissolved in acetone (10 ml) wasadded 2N Jones reagent (10 ml) while cooling on ice, and the mixture wasstirred for 4 hours at room temperature. Ethyl acetate was added, andthe resultant mixture was washed with water. The organic layer wasextracted with a sat. aq. K₂ CO₃, and the aqueous layer was washed withethyl acetate. The washed material was acidified with dilute HCl, againextracted with ethyl acetate, then washed with saturated brine. Dryingover anhydrous magnesium sulfate and concentrating under reducedpressure yielded 1.27 g of 3-benzyloxypropionic acid as a colorlesscrystals.

¹ H-NMR(CDCl₃, ppm, TMS): 2.67(2H, t, J=6.4 Hz), 3.75(2H, t, J=6.4 Hz),4.55(2H, s), 7.25-7.38(5H, m) IR(KBr)cm⁻¹ : 3430, 3032, 2927, 1716,1455, 1366, 1235, 1201, 1104, 1072, 739, 698

(2) Oxalyl chloride (880 mg) was added to a solution of3-benzyloxypropionic acid (1.04 g) in benzen (10 ml). Subsequently,dimethylformamide (100 mg) was added. After the resultant mixture wasstirred for 30 minutes at room temperature, benzen was distilled off.Azeotropic distillation was performed twice through use of benzen (10ml), and the resultant residue was dissolved in tetrahydrofuran (10 ml).To the solution were added 3-methyl-3-oxetanyl-methyl alcohol (620 mg)and then triethylamine (620 mg). The mixture was stirred for 5 hours atroom temperature. Ethyl acetate was added to the reaction mixture,followed by washing with sat. aq. K₂ CO₃, water, 1N-HCl, water, andsaturated brine and then drying over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethyl acetate-hexane 2:1),to give 1.01 g of 3-methyl-3-oxetanylmethyl 3-benzyloxypropionate as apale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.32(3H, s), 2.67(2H, t, J=6.4 Hz), 3.77(2H,t, J=6.4 Hz), 4.20(2H, s), 4.36(2H, d, J=6.1 Hz), 4.51(2H, t, J=6.1 Hz),4.53(2H, s), 7.24-7.39(5H, m); IR(CDCl₃)cm⁻¹ : 3012, 2968, 2878, 1736,1455, 1379, 1365, 1249, 1183, 1103, 1072, 981, 834

(3) 3-Methyl-3-oxetanylmethyl 3-benzyloxypropionate (521 mg) wasdissolved in dichloromethane under an argon atmosphere, andtrifluoroborane-diethylether was added thereto at -15° C. The mixturewas stirred for 5 hours at -15° C. Triethylamine (280 μl) was added tothe reaction mixture, and stirring was continued for 15 minutes.Subsequently, diethylether (3 ml) was added. The precipitating crystalswere removed from the reaction mixture by filtration, then the motherliquid was concentrated under reduced pressure. The residue was purifiedby alumina column chromatography (ethyl acetatehexane 1:3), to give 385mg of 1-(2-benzyloxyethyl)-4-methyl-2,6,7-trioxabicyclo-[2.2.2]octane asa colorless solid.

¹ H-NMR(CDCl₃, ppm, TMS): 0.79(3H, s), 2.07(2H, t, J=7.6 Hz), 3.62(2H,t, J=7.6 Hz), 3.88(6H, s), 4.51(2H, s), 7.27-7.35(5H, m); IR(CHCl₃)cm⁻¹: 3446, 2937, 2881, 1475, 1454, 1371, 1347, 1252, 1192, 1126, 1099,1052, 1005, 990, 944, 907, 745

(4) To liquid ammonia (35 ml) was added, under an argon atmosphere, asolution of1-(2-Benzyloxyethyl)-4-methyl-2,6,7-trioxabicyclo-[2.2.2]octane (3.54 g)in anhydrous tetrahydrofuran (8 ml). Metallic sodium (500 mg) was thenadded thereto, and the resultant mixture was stirred for 3 hours at -78°C. After ammonium chloride was added to the reaction mixture, ammoniawas evaporated, and tetrahydrofuran was evaporated under reducedpressure. The residue was washed with ether, and the resultant solid wasadded to saturated brine and extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, to give1-(2-hydroxyethyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (1.4 g) asa pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 0.82(3H, s), 1.95(2H, t, J=5.4 Hz), 3.75(2H,brt, J=5.4 Hz), 3.93(6H, s)

(5) Sodium hydride (35 mg) was added to a solution of1-(2-hydroxyethyl)-4-methyl-2,6,7-trioxabicyclo-[2.2.2]octane (50 mg) indimethylsulfoxide (2 ml). To the mixture, after being stirred for 10minutes at room temperature, was added4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide(93 mg). The resultant mixture was stirred for 5 hours at 70° C. Afterthe reaction mixture was cooled, saturated aqueous citric acid solution(200 μl) was added thereto, followed by stirring for 1 hour at roomtemperature. Ethyl acetate was added to the reaction mixture. Theresultant mixture was successively washed with water and saturatedbrine.

The organic layer was dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (chloroform-methanol 7:1),to give 40 mg of 3-hydroxy-2-hydroxymethyl-2-methylpropyl3-[6-(4-t-butylphenyl-sulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionateas a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 0.75(3H, s), 1.29(9H, s), 2.75(2H, t, J=6.1Hz), 3.44(2H, d, J=11.0 Hz), 3.48(2H, d, J=11 Hz), 3.96(3H, s), 4.14(2H,s), 4.81(2H, t, J=6.1 Hz), 6.85(1H, m), 6.95-7.06(2H, m), 7.12(1H, m),7.37-7.44(3H, m), 3.37(2H, d, J=8.1 Hz), 9.01(2H, d, J=4.9 Hz)IR(KBr)cm⁻¹ : 3412, 2965, 1735, 1580, 1560, 1500, 1385, 1255, 1175,1082, 752, 630, 576

The thus-obtained Compound No. 109 was added to HCl-acetone and stirred,to give a Compound No. 3.

Example 123 (Synthesis of Compound No. 118)

(1) Propanediol (532 mg) was dissolved in anhydrous dimethylformamide (5ml) under an argon atmosphere, and sodium hydride (50% dispersion inoil) (21 mg) was added to the resultant solution at room temperature.

A solution of4-t-butyl-N-[6-chloro-2-(4,6-dimethoxy-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide(409 mg) in anhydrous dimethylformamide (2.4 ml) was added dropwise tothe above mixture while being cooled on ice. The resultant mixture wasstirred for 3.5 hours at 60° C. The reaction mixture was poured intocold 1N HCl, and extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=20/1) to give obtain4-t-butyl-N-[2-(4,6-di(3-hydroxypropyloxy)-2-pyrimidinyl)-6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide(250 mg) as a colorless oil.

(2) To a solution of anhydrous ethanol (0.0246 ml) in anhydrousdimethylformamide (1 ml) was added, under an argon atmosphere, sodiumhydride (50% dispersion in oil) (6 mg) at room temperature. A solutionof4-t-butyl-N-[2-(4,6-di(3-hydroxypropyloxy)-2-pyrimidinyl)-6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide(15 mg) in anhydrous dimethylformamide (0.7 ml) was added dropwise tothe above mixture while being cooled on ice. The resultant mixture wasstirred for 1.5 hours at room temperature.

The reaction mixture was poured into cold 1N HCl, and extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, then concentrated under reduced pressure.The residue was purified by silica gel preparative thin-layerchromatography (chloroform/methanol =15/1) to give4-t-butyl-N-[2-(4,6-diethoxy-2-pyrimidinyl)-6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide(8 mg) as a colorless oil.

(3)

The procedure described in Example 3 was repeated using4-t-butyl-N-[2-(4,6-diethoxy-2-pyrimidinyl)-6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide(19 mg), to obtain 3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-diethoxy-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionic acid (9.1 mg) as a colorless oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 1.45(6H, t, J=7.0 Hz), 2.76(2H,t, J=6.3 Hz), 3.87(3H, s), 4.56(4H, q, J=7.0 Hz), 4.73(2H, t, J=6.3 Hz),6.12(1H, s), 6.73-7.07(4H, m), 7.38(2H, d, J=8.9 Hz), 8.07-8.28(2H, br);IR(CHCl₃)cm⁻¹ : 3520, 3373, 3201, 2967, 1719, 1619, 1592, 1576

Example 124 (Synthesis of Compound No. 119)

The procedure described in Example 123 was repeated using4-t-butyl-N-[2-(4,6-di(3-hydroxypropyloxy)-2-pyrimidinyl)-6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-benzenesulfonamideand isopropyl alcohol, to obtain3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-diisopropyloxy-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionicacid (23 mg) as a pale yellow oil.

¹ H-NMR(CDCl₃, ppm, TMS): 1.35(9H, s), 1.47(12H, d, J=6.3 Hz), 2.84(2H,t, J=6.0 Hz), 3.92(3H, s), 4.79(2H, t, J=6.0 Hz), 5.51-5.65(2H, m),6.11(1H, s), 6.76-7.12(4H, m), 7.43(2H, d, J=8.5 Hz), 8.04-8.28(2H, br)IR(CHCl₃)cm⁻¹ : 3516, 3367, 2968, 1719, 1619, 1591, 1575

Example 125 (Synthesis of Compound No. 125)

(1) Compound No. 2(135 mg) and N,O-dimethylhydroxyamine.HCl (93 mg) weredissolved in DMF (3 ml). Triethylamine (0.30 ml) and 50%propanephosphonic acid anhydride in ethyl acetate (0.12 ml) were addedthereto while being cooled on ice. The mixture was stirred for 1 hourwhile being cooled on ice, and then overnight at room temperature.

The reaction mixture was concentrated under reduced pressure. Theresidue was extracted with ethyl acetate and washed, with 1N HCl, sat.aq. NaHCO₃, water, and saturated brine, dryed over anhydrous sodiumsulfate and concentration under reduced pressure to give 111 mg ofN-methyl-N-methoxy-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamide(yield 79%) as a colorless powder.

(2)N-methyl-N-methoxy-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenyl)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]acetamide(36 mg) was dissolved in anhydrous THF (2 ml) under an argon atmosphere.To the solution was added dropwise a solution (0.079 ml) of3N-methylmagnesium bromide in ether at -30° C. The mixture was stirredat -30° C. for 20 minutes.

Saturated ammonia water was added, and extracted with ethyl acetate. Theaqueous layer was acidified with 2N HCl, and extracted with ethylacetate. The organic layers were combined together, washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure.

The residue was purified by silica gel preparative thin-layerchromatography (chloroform/ethyl alcohol=5/1), to give4-t-butyl-N-[5-(2-methoxyphenoxy)-6-(2-oxopropyloxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide(16 mg) as a pale yellow powder (yield 47%).

¹ H-NMR(CDCl₃, ppm, TMS): 1.29(9H, s), 2.12(3H, s), 3.96(3H, s),5.09(2H, s), 6.84-7.16(4H, m), 7.40-7.45(3H, m), 8.38(2H, brs), 8.99(2H,d, J=4.8 Hz); IR(CHCl₃)cm⁻¹ : 3371, 3198, 2968, 1739, 1580, 1559, 1499,1470

Test Example 1

Endothelin Binding Inhibition Experiment

Preparation of receptor membrane samples (ET_(A)) from smooth muscles ofporcine thoracic aorta:

Porcine thoracic aorta which was separated from the fatty tissue andthen was removed endothelium with gauze was minced, and then homogenizedin three times the volume of Tris-HCl buffer (pH 7.4) (buffer A)containing 0.25 M sucrose, 3 mM ethylenediaminetetraacetic acid, 5 μg/mlof aprotinin, 10 μg/ml of pepstatin A, 10 μg/ml of leupeptin, and 0.1 μMp-amidinophenyl-methanesulfonyl fluoride. After centrifugation for 30minutes at 1,000×g, the supernatant was further centrifuged for 30minutes at 100,000×g. The pellets were suspended in buffer A, andrecentrifuged for 30 minutes at 100,000×g. The pellets were suspended inbuffer A and the suspension was stored at -80° C.

¹²⁵ I-Endothelin-1 Binding Assay:

The thus-obtained membrane sample (1 μl ) was incubated together with¹²⁵ I-endothelin-1 (2×10⁻¹¹ M) and various concentrations of thecompounds, for 2 hours at 25° C., in 250 μl in total volume of 50 mMTris-HCl buffer (pH 7.4) containing 0.5 % bovine serum albumin. Theincubated mixture was filtered by use of an HVPP filters (pore size 0.45μm, product of Milipore). The filters were washed with cold buffer Afour times, and then measured with a gamma-ray counter (Aroka AutowellGamma System ARC-251). Preparation of receptor membrane sample (ET_(B))from rat brain and assay of ¹²⁵ I endothelin-1:

Rat brain tissue was minced, and a crude receptor membrane sample wasprepared in a manner similar to that used in the aforementioned case ofporcine thoracic aorta. Also, ¹²⁵ I-endothelin-1 assay was performed inthe same manner as described above.

The results of the thus-performed endothelin binding inhibitionexperiment for each of the two receptors are shown in Table 10.

                  TABLE 10                                                        ______________________________________                                                       IC.sub.50 (μM)                                              Compound No.     ET.sub.A                                                                              ET.sub.B                                             ______________________________________                                        2                9.4     0.8                                                  9                0.72    2.9                                                  10               0.51    0.65                                                 12               0.32    0.82                                                 14               0.82    0.0028                                               15               3.2     0.016                                                18               0.15    0.023                                                25               1.9     0.037                                                29               3.1     0.03                                                 34               0.39    0.22                                                 38               16.9    0.019                                                48               0.16    0.00075                                              53               0.098   0.00082                                              92               0.0095  0.1                                                  ______________________________________                                    

Test Example 2

1) ET_(A) Receptor Antagonizing Action

The thoracic aorta was removed from a male SD rat, and ring sample ofthe aorta each having a width of 3 mm were prepared. Each ring, whilesubjected to a static tension of 2 g, was suspended in an organ bathfilled with a 37° C. Krebs-Henseleit solution (NaCl 118.4 mM, KCl 14.7mM, CaCl₂ 2.5 mM, MgSO₄ 1.2 mM, KH₂ PO₄ 1.2 mM, NaHCO₃ 25.0 mM, glucose10.0 mM aerated with a gas mixture of 95% 02 and 5% C0₂. The vascularsample was pretreated for 20 minutes by use of either 10⁻⁷ -10⁻⁵ MCompound No. 92 or a solvent therefor. Subsequently, endothelin-1dissolved in brine containing 0.1% bovine serum albumin was added in acumulative manner, and isometric contraction was observed in the rangeof 1 to 100 ng/ml (4×10⁻⁹ to 4×10⁻⁸ M) of endothelin, to therebyinvestigate the effects of the compounds. FIG.1 shows contractionresponses (%) normalized with respect to the contraction responseobtained through application of 80 mM KCl.

2) ET_(B) Receptor Antagonizing Action

The pulmonary artery was removed from a male NZW rabbit, and each ofarterial samples prepared as described above was suspended in an organbath in a manner similar to that described above, with the applicationof a static tension of 1 g. The sample was pretreated for 30 minutes byuse of either 3×10⁻⁸ -3×10⁻⁷ M Compound No. 68 or a solvent therefor.Subsequently, sarafotoxin (SRTX) S6c, which is a selective agonist forET_(B) receptor, was added was added in a cumulative manner, andisometric contraction was observed in the range of 10⁻¹² to 3×10⁻⁷ Msarafotoxin S6c, to thereby investigate the effects of the compounds.FIG.2 shows contraction responses (%) normalized with respect to thecontraction response obtained through application of 60 mM KCl.

From the above experiments, it was found that the compounds of thepresent invention exhibit remarkable antagonizing action on ET_(A) andET_(B) receptors present in vascular samples.

Industrial Applicability

The novel pyrimidine derivatives (1) of the present invention exhibitstrong binding inhibitory activity against endothelin having very strongvasoconstrictive effect and cell proliferation effect. Therefore, thecompounds are effective as remedies for various endothelin-relateddiseases and disorders including heart diseases such as ischemic heartinfarction, congestive heart failure, arrhythmia, and unstable angina;airway diseases such as asthma; hypertonia such as pulmonaryhypertension, renal hypertension, and hypertension accompanying organtransplantation; circulatory diseases such as subarachnoid hemorrhageand vasospasm; kidney diseases such as acute and chronic renal failure;diabetes, hyperlipemia, and other diseases that are accompanied byvascular lesion; arteriosclerosis; liver diseases such asalcohol-induced liver disorders; gastrointestinal disorders such asthose of gastric mucosa; bone diseases; prostatic hypertrophy; urinarydisorders; cancer; and skin diseases concurrent with proliferation ofmelanocytes.

We claim:
 1. A pyrimidine derivative of the following formula (1) or asalt of the derivative: ##STR107## wherein R¹ represents a lower alkylgroup; each of R² and R³, which are identical to or different from eachother, represents a hydrogen atom, a lower alkyl group, or a loweralkoxyl group; each of R⁴ and R⁵, which are identical to or differentfrom each other, represents a hydrogen atom or a lower alkyl group; R⁶represents a lower alkyl group, --OR⁷, or --NR⁸ R⁹ ; and n is a numberbetween 0 and 3 inclusive;wherein R⁷ represents:a hydrogen atom; a loweralkyl group; a phenyl group which may have a substituent, thesubstituent selected from the group consisting of C₁₋₆ alkyl groups,C₁₋₆ alkoxyl groups, and a halogen atom; an aralkyl group which may havea substituent, the group being selected from the group consisting ofphenylalkyl group, naphthylalkyl group, biphenylalkyl group and indanylgroup, and the substituent being selected from the group consisting ofhydroxy, C₁ -C₆ alkyl C₁ -C₆ alkoxyl, C₁ -C₃ alkylenedioxy, halogen,nitro, trifluoromethyl, and cyano; and each of R⁸ and R⁹, which areidentical to or different from each other, represents:a hydrogen atom; ahydroxyl group; a lower alkyl group which may have a substituent, thegroup being selected from the group consisting of a linear, branched orcyclic alkyl group having 1-6 carbon atoms, the substituent being one tothree halogen atoms or hydroxyl groups; a lower alkenyl group which mayhave a substituent, the group being selected from the group consistingof linear, branched, or cyclic alkenyl group having 2-6 carbon atoms,the substituent being one to three halogen atoms or hydroxyl groups; anaryl group which may have a substituent, the group being selected fromthe group consisting of phenyl and naphthyl, the substituent being oneto three C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₁₋₆ alkoxyl groups,C₁₋₆ alkylthio groups, halogen atoms, hydroxy groups, amino groups,nitro groups, alkoxycarbonyl groups or C₁₋₆ haloalkyl groups; an aralkylgroup which may have a substituent, the group being selected from thegroup consisting of phenylalkyl group, naphthylalkyl group,biphenylalkyl group and indanyl group, and the substituent beingselected from the group consisting of hydroxy, C₁ -C₆ alkyl, C₁ -C₆alkoxyl , C₁ -C₃ alkylenedioxy, halogen, nitro, trifluoromethyl, andcyano; an amino group which may have a substituent, the substituentbeing selected from the group consisting of phenyl, C₁ -C₆ alkylsubstituted phenyl, pyridyl, and C₁ -C₆ alkyl; or a heterocyclic groupor heterocyclic alkyl group, which may have a substituent, the groupbeing selected from the group consisting of furyl group, thienyl group,pyrazolyl group, thiazolyl group, thiadiazolyl group, imidazolyl group,pyridyl group, pyrimidinyl group, pyrazinyl group, furylalkyl group,thienylalkyl group, pyrazolylalkyl group, thiazolylalkyl group,imidazolylalkyl group, pyridylalkyl group and pyrimidinylalkyl group,the substituent being selected from the group consisting of C₁ -C₆alkyl, C₁ -C₆ alkoxyl, C₁ -C₆ haloalkyl, and halogen; or R⁸ and R⁹ maybe linked to each other so as to form a 5-to 7-membered ring along withtheir adjacent nitrogen atom.
 2. A pyrimidine derivative as described inclaim 1 or a salt of the derivative, wherein R¹ is an isopropyl group ora tert-butyl group.
 3. A pharmaceutical composition comprising apyrimidine derivative as described in claim 1 or a salt of thederivative and a pharmaceutically acceptable carrier.
 4. The pyrimidinederivative as described in claim 1 or a salt of the derivative,wherein:the phenyl group which may have a substituent is selected fromthe group consisting of methylphenyl, ethylphenyl, isopropylphenyl,methoxyphenyl, ethoxyphenyl, chlorophenyl, bromophenyl and fluorophenyl;the aralkyl group which may have a substituent is selected from thegroup consisting of benzyl phenethyl, phenylpropyl, naphthylmethyl,naphthylethyl, biphenylmethyl and indan-1-yl groups, these groups beingoptionally further substituted by one to three groups selected from thegroups consisting of chloro, fluoro, methoxy, ethoxy, methyl, ethyl,nitro, cyano and trifluoromethyl groups; the lower alkenyl group whichmay have a substituent is selected from the group consisting of vinyl,propenyl and isobutenyl groups; the aryl group which may have asubstituent is selected from the group consisting of phenyl, naphthyl,mono- or di-chlorophenyl, mono- or di-fluorophenyl, mono-, di-, ortri-methoxyphenyl, mono- or di-methylphenyl, mono- or di-ethylphenyl,mono- or di-isopropylphenyl, tert-butylphenyl, isopropenylphenyl,hydroxyphenyl, nitrophenyl, aminophenyl, ethoxycarbonylphenyl andmethylthiophenyl; the amino group which may have a substituent isselected from the group consisting of phenylamino, C₁₋₆alkyl-substituted phcnylamino, pyridylamino, and C₁₋₆ alkylamino groups;the heterocyclic group which may have a substituent and theheterocyclic-alkyl group which may have a substituent is selected fromthe group consisting of furyl, thienyl, pyrazolyl, thiazolyl, pyridyl,pyrimidinyl, pyrazinyl furfuryl, thienylmethyl, pyrazolylmethyl,thiazolylmethyl, imidazolylmethyl, pyridylmethyl and pyrimidinylmethylgroups, all of which groups is optionally further substituted by a groupselected from the group consisting of methyl, ethyl, methoxy, ethoxy,chloro, fluoro and trifluoromethyl; the 5-to 7-membered ring formed by--NR⁸ R⁹ is selected from the group consisting of pyrrolidinyl,piperidinyl, and perhydroazepinyl groups.
 5. The pyrimidine derivativeas described in claim 1, the pyrimidine derivative being any oneofN-(2-isopropylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide,N-(2-pyridyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide,N-(2,6-dimethylphenyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide,N-(2-pyridyly)-4-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]butyramide,N-(2-pyrazinyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide,N-(2-thiazolyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide,N-(2-methylallyl)-3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionamide,orN-(2-pyridyl)-3-[6-(4-t-butylphenylsulfonylamino)-2-(4,6-dimethyl-2-pyrimidinyl)-5-2-methoxyphenoxy)-4-pyrimidinyloxy]propionamide.6. A pharmaceutical composition comprising a pyrimidine derivative asdescribed in claim 2 or a salt of the derivative and a pharmaceuticallyacceptable carrier.